Nihar R. Desai, MD, MPH

VICTORION-INCEPTION Study

PCSK9i are an important class of medications used to aggressively lower LDL-C levels, especially in high-risk patients, including those with a history of ACS. Recent data from the 

 study, presented in 2024, provides new insights into the cardiovascular outcomes associated with initiating PCSK9i in patients after a recent ACS event.

As previously discussed, 2 PCSK9i are currently approved for use:

Both are monoclonal antibodies that target and inhibit the PCSK9 protein, allowing for increased LDL receptor availability and enhanced LDL-C clearance from the bloodstream. These agents are particularly beneficial in high-risk cardiovascular patients who need additional LDL-C level lowering beyond what statins can provide.

Insights from the VICTORION-INCEPTION Study:

PCSK9i (specifically inclisiran) in patients with a 

. The study aimed to assess whether early initiation of PCSK9i could 

 in this high-risk population, given the significant burden of LDL-C levels and ongoing atherosclerotic plaque instability following ACS.

: The trial enrolled patients who had experienced an ACS event within the past 

: Patients were randomly assigned to receive inclisiran or a 

, in addition to standard care, including statins.

composite of major adverse cardiovascular events (MACE)

, including cardiovascular death, myocardial infarction, stroke, and unstable angina leading to hospitalization.

:
The study found that the addition of inclisiran to standard therapy in post-ACS patients led to a 

 compared with placebo. This underscores the benefit of aggressive LDL-C level lowering in reducing future cardiovascular risk following an ACS event.

 in LDL-C levels, typically lowering LDL-C by approximately 

 from baseline. This reduction was associated with a marked decrease in the risk of recurrent cardiovascular events, highlighting the importance of intensive lipid management.

, with no major safety concerns. The incidence of adverse effects was similar between the inclisiran and placebo groups, supporting the safety of adding PCSK9i to routine post-ACS care.

:
Intracoronary imaging data from the study suggested that the early use of inclisiran may 

, further reducing the risk of future coronary events. This aligns with the broader body of evidence showing that aggressive LDL-C level reduction can have beneficial effects on coronary atherosclerosis.

 study provides strong evidence supporting the 

PCSK9i (specifically inclisiran) in patients with a recent ACS event. The study demonstrated 

lower rates of major cardiovascular events

, establishing the role of PCSK9i in improving outcomes for high-risk post-ACS patients. The findings further solidify the concept that 

 plays a crucial role in the secondary prevention of cardiovascular events.

Videos

Panelists discuss how the VICTORION-INCEPTION study highlights the benefits of early initiation of PCSK9 inhibitors (PCSK9i; specifically inclisiran) in patients with post-acute coronary syndrome (ACS), demonstrating significant low-density lipoprotein cholesterol (LDL-C) level reduction, lower rates of major cardiovascular events, and improved outcomes through aggressive lipid-lowering therapy.

PCSK9 Inhibitors

PCSK9i are a class of monoclonal antibodies that effectively lower LDL-C levels and are particularly useful for patients with high cardiovascular risk, including those with acute coronary syndrome (ACS) or familial hypercholesterolemia. Currently, 2 PCSK9i have been approved for clinical use.

: Alirocumab is a fully human monoclonal antibody that targets PCSK9, preventing it from binding to LDL receptors on hepatocytes, which enhances the liver’s ability to clear LDL-C from the blood.

heterozygous familial hypercholesterolemia

atherosclerotic cardiovascular disease (ASCVD)

 who need additional LDL-C level lowering, particularly in those not achieving sufficient reduction with statins or who are statin-intolerant.

: Alirocumab is typically administered via 

, depending on the patient's LDL-C level and response to treatment.

: Similar to alirocumab, evolocumab is a monoclonal antibody that inhibits PCSK9, allowing for increased LDL receptor availability on liver cells and enhancing LDL-C clearance.

: Evolocumab is approved for patients with 

, and those requiring additional LDL-C level lowering beyond what statins alone can provide. It is also approved for 

: Evolocumab is typically administered via 

, depending on the patient’s needs. In some cases, more frequent dosing may be necessary depending on LDL-C level goals.

Both medications have demonstrated significant efficacy in lowering LDL-C levels and improving cardiovascular outcomes

 in high-risk patients, particularly those who do not achieve adequate LDL-C level reduction with statin therapy alone. These PCSK9 inhibitors are generally well tolerated, with adverse effects being relatively rare and typically mild, such as injection site reactions.

 are the 2 PCSK9i currently available, offering valuable options for intensive LDL-C level lowering in high-risk patients, especially those with statin resistance or intolerance.

Panelists discuss how the 2 available PCSK9 inhibitors (PCSK9i), alirocumab and evolocumab, provide effective low-density lipoprotein cholesterol (LDL-C) level lowering for high-risk patients, including those with acute coronary syndrome or familial hypercholesterolemia, especially when statin therapy alone is insufficient or not tolerated.

Benefits of PCSK9i Demonstrated in Intracoronary Imaging

Recent RCTs have highlighted the significant benefits of monoclonal antibody therapy with PCSK9i in patients with ACS. These trials have shown that PCSK9i not only effectively lower LDL-C levels rapidly but also positively impact coronary atherosclerosis, as assessed by intracoronary imaging techniques.

Topline Results of Recent RCTs on PCSK9i in Patients With ACS:

: Several studies have demonstrated that PCSK9i lead to 

rapid and substantial reductions in LDL-C

 in patients with ACS. These reductions occur within weeks of initiating therapy, offering an aggressive approach to lowering LDL-C levels post-ACS, which is essential for secondary prevention of cardiovascular events.

: Intracoronary imaging techniques, such as intravascular ultrasound and optical coherence tomography, have shown that treatment with PCSK9i can 

reduce the burden of coronary atherosclerosis

 in patients post-ACS. Studies such as the 

 trials have demonstrated that significant LDL-C level reduction with PCSK9i leads to 

, which is crucial for preventing recurrent cardiovascular events.

Reduced Risk of Major Cardiovascular Events

: In addition to the LDL-C level and atherosclerosis improvements, these trials have also shown that PCSK9i treatment significantly 

reduces the risk of major adverse cardiovascular events 

in patients who are at a high risk for ACS. The data supports the idea that the benefits of lowering LDL-C levels extend beyond just cholesterol reduction and involve real, measurable improvements in cardiovascular outcomes.

: The trials also confirm that PCSK9i have a 

, with no significant increase in major adverse effects such as neurocognitive decline or cancer, which had been concerns in some earlier studies with other lipid-lowering treatments. This has solidified their role as a viable option for patients who require more intensive lipid-lowering therapy.

: For patients who are not achieving adequate LDL-C level reduction with high-intensity statins alone or are statin-intolerant, 

PCSK9i therapy provides an important adjunct

. Combining PCSK9i with statins offers an enhanced approach to reaching target LDL-C levels and reducing residual cardiovascular risk.

In conclusion, the topline results from recent RCTs demonstrate that PCSK9i not only 

positive changes in coronary atherosclerosis

 in patients post-ACS. These findings underscore the growing role of PCSK9i in optimizing care for patients who are at a high risk for ACS, particularly when traditional therapies are insufficient.

Panelists discuss how recent randomized clinical trials (RCTs) highlight the significant benefits of PCSK9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS), showing rapid low-density lipoprotein cholesterol (LDL-C) reduction, positive impacts on coronary atherosclerosis, and a reduction in major cardiovascular events.

Challenges to  Reaching LDL-C Goal

Achieving the LDL-C target level within 4 to 6 weeks after an ACS event is a key component of secondary prevention. However, reaching this goal in a timely manner remains a challenge for many patients, despite the availability of effective treatment options.

Percentage of Patients Achieving LDL-C Level Goal 4 to 6 Weeks After ACS:

The percentage of patients achieving the recommended LDL-C target level within 4 to 6 weeks post-ACS varies but studies suggest that 

 reach the desired levels in this short time frame. Typically, 

 meet the less than 70 mg/dL target level after 4 to 6 weeks of high-intensity statin therapy. This figure can be lower in certain populations, particularly those with multiple risk factors or those not receiving optimal treatment.

Current Challenges in Getting Patients to LDL-C Level Goal:

: One of the most common barriers to achieving LDL-C level goals is 

 to prescribed statin therapy. Many patients either discontinue therapy due to adverse effects (eg, muscle pain) or fail to take the medication regularly, leading to suboptimal LDL-C level reduction.

: Despite guidelines recommending high-intensity statin therapy post-ACS, some patients are not prescribed or do not tolerate the appropriate intensity. This results in inadequate LDL-C level lowering, especially in high-risk patients who need aggressive treatment.

: Some patients may have concerns about the potential adverse effects of statins or other lipid-lowering medications, leading to their nonadherence or reluctance to start treatment. Additionally, a 

 about the importance of LDL-C management in preventing future cardiovascular events may contribute to poor adherence.

: Patients with multiple comorbidities, such as diabetes or kidney disease, may be on various medications that interact with statins or other cholesterol-lowering drugs, limiting the dose or effectiveness of therapy.

: In some cases, patients who do not reach their LDL-C target level with statins alone may require additional medications, such as ezetimibe or PCSK9 inhibitors. However, access to these medications can be limited due to cost, insurance coverage, or availability, making it difficult for all patients to achieve the optimal LDL-C level.

: Inconsistent follow-up and monitoring of LDL-C levels post-ACS may contribute to suboptimal care. Regular follow-up visits are crucial to assess whether the patient is reaching their LDL-C goal level and to adjust therapy if necessary.

In summary, while achieving LDL-C level goals within 4 to 6 weeks post-ACS is crucial for preventing recurrent cardiovascular events, significant challenges exist in reaching these targets due to adherence issues, inadequate treatment intensity, patient concerns, and access to necessary therapies. Addressing these barriers through education, improved monitoring, and personalized care plans is essential to improving outcomes.

Panelists discuss how achieving the low-density lipoprotein cholesterol (LDL-C) target level within 4 to 6 weeks after an acute coronary syndrome (ACS) event remains challenging for many patients due to factors such as suboptimal statin adherence, inadequate treatment intensity, patient concerns, and limited access to additional therapies.

Nihar R. Desai, MD, MPH

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