PCSK9 inhibitor treatment and outcomes

PCSK9i mAb therapy use was associated with a lower rate of ischaemic events and mortality rates vs. no PCSK9i* in a study of over 19,000 ASCVD patients without prior ischaemic events.¹

Discover the findings from the methodologically advanced⁺ real-world OPTIMUS-CLASS study, part of the broader OPTIMUS (Outcomes and PrevenTlon Programme with PCSK9i Monoclonal Antibodies in ASCVD PopUlation without Prior ISchaemic Events) programme.^1,2

• 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 can reduce LDL-C levels when used alone or in combination with statins^3,4
• While clinical trials have established the effectiveness of PCSK9i mAbs across the different stages of ASCVD, real-world data remain limited¹
• The OPTIMUS-CLASS study provides real-world evidence on the 5-year impact of PCSK9i mAbs^‡ on ischaemic events and all-cause mortality in ASCVD patients without any prior ischaemic events¹

The baseline characteristics for the PCSK9i mAb^‡ group and no PCSK9i* group were well balanced.¹

PCSK9i mAb^‡ treatment was associated with a 30.9% relative reduction in the risk of nonfatal MI, nonfatal IS or all-cause mortality in ASCVD patients without a prior ischaemic event.¹

The estimated 5-year event rate for the composite endpoint of nonfatal MI, nonfatal IS or all-cause mortality was significantly lower in the PCSK9i mAb^‡ group vs. the no PCSK9i* group.¹

The 5-year event rate was 17.5% (95% CI 15.5, 19.5) in the PCSK9i mAb^‡ group (n=6,545) vs. 25.4% (95% CI 23.6, 27.1) in the no PCSK9i* group (n=13,125), resulting in a significant 30.9% relative reduction in the risk of first MACE (ARR 7.8%) (P<0.0001).¹

Estimated event rates over time for the primary endpoint with parametric G-formula (ITT)¹

A reduction in 5-year event rate was also seen in the PCSK9i mAb^‡ group across each individual endpoint, with 28.3%, 26.4% and 28.5% RRR observed across nonfatal MI, nonfatal IS and all-cause mortality event rates, respectively, vs. the no PCSK9i* group.⁵

Individual endpoint 5-year event rates (ITT)⁵

Adapted from Bhatt et al. 2026. Supplementary Material.

In the ITT population, patients in the PCSK9i mAb^‡ group went from an LDL-C level of 117.8 mg/dL to 78.0 mg/dL at follow-up after 5 years.¹ This resulted in a 39.8 mg/dL absolute reduction in LDL-C, representing a 33.8% percentage reduction.¹ These findings are consistent with the CTT^††, which demonstrated a strong association between RRR in MACE per 1 mmol/L reduction in LDL-C.⁶

Relationship between LDL-C reduction and relative risk reduction in ischaemic events compared to CTT meta-analysis¹

When looking at patients who were treated with or without statins, both the with statins and without statins PCSK9i mAb^‡ groups had lower cumulative event rates than their equivalent no PCSK9i* groups.⁵ Current study 30.9% (95% CI 22.3%, 38.1), CTT RRR 28.8% (95% CI 22.6%, 35.0%)

The falsification analysis, used to support the validity of data, found no significant difference between the PCSK9i mAb^‡ and no PCSK9i* groups.¹

To help determine whether the lower rate of MACE with PCSK9i mAbs^‡ VS. no PCSK9i* was confounded by other factors, the study assessed whether PCSK9i mAbs^‡ vs. no PCSK9i* was associated with any unexpected benefit in the falsification endpoint, defined as composite of cancer, hospitalised major bleeding or hospitalised sepsis.¹ At 5 years, the incidence of the falsification endpoint was similar in the PCSK9i mAbs^‡ group (9.1%) and no PCSK9i* group (10.2%), supporting the validity of the MACE data.¹

Falsification analysis¹

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

+RWE studies can vary substantially in their methodological approaches, which may contribute to heterogeneity or unexpected findings across analyses. Ensuring that key epidemiological principles – such as appropriate time zero definition, new user design considerations, handling of open claims data, and assessment of potential time related biases – are rigorously applied remains essential to generate reliable insights. High quality RWE therefore depends on robust and methodically advanced approaches such as propensity score matching and G-computation used in the study.

‡PCSK9i mAb represents alirocumab or evolocumab.¹

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

§Represents health plan in the US offered by a private company that contracts with Medicare to provide patients with hospital and medical insurance benefits.¹

||Includes any type of disease that is non-coronary, non-cerebrovascular, or does not involve the lower extremities or aorta.¹

¶Includes dialysis or renal transplant.¹

**Includes clopidogrel, ticagrelor, and prasugrel; 98.8% use in this category was for these agents. Additional agents were anagrelide, cilostazol, dipyridamole (including aspirin combo), pentoxifylline and vorapaxar sulphate.¹

++CTT relative risk reduction = 28% (95% CI 22, 34) per mmol/L reduction in LDL-C.¹