Even with maximum intensity statin/ezetimibe treatment, most of the patients with familial hypercholesterolemia (FH) do not achieve the latest low-density lipoprotein cholesterol (LDL-C) targets; highlighting the necessity for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and additional LDL-C lowering therapy.

<h2>Key Takeaway</h2>
<ul>
 <li>In this cohort of patients with FH, only 2.7% had achieved the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) 2019-recommended LDL-C target.</li>
 <li>More than half of FH patients (55.9%) would be eligible for add-on PCSK9i therapy despite receiving rosuvastatin/ezetimibe 40/10 mg/day.</li>
 <li>Following theoretical administration of a PCSK9i, 42.4% of patients would still be eligible for additional LDL-C lowering therapies.</li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>ESC/EAS 2019 guidelines recommend more aggressive LDL-C targets for patients with FH.</li>
 <li>PCSK9i are recommended in very high-risk patients with FH if the treatment goal is not attained on maximal tolerated statin plus ezetimibe and in FH patients who cannot tolerate statins.</li>
 <li>However, it is currently unknown how many patient with FH are candidates for PCSK9i under 2019 ESC/EAS guidelines and in how many of them a fourth LDL-C lowering agent will be required.</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>This study analyzed the data from Hellas-FH registry, which is based on a network of sites that are distributed throughout Greece.</li>
 <li>Patients with at least a possible diagnosis of FH (Dutch Lipid Clinic Network [DLCN] score ≥3) were enrolled in the registry. Patients homozygous for FH were excluded.</li>
 <li>Primary endpoint: Rate of LDL-C target achievement</li>
 <li>Secondary endpoint: Impact of a theoretical treatment switch to rosuvastatin/ezetimibe 40/10 mg/day, and the rate of eligibility for PCSK9 inhibitor and the need for extra LDL-C lowering treatment.</li>
</ul>

<h2>Key Results</h2>
<ul>
 <li>In total, 1,694 adult patients (860 male) were enrolled in this analysis, mean age of 50.8 ± 14.7 years old. 
 <ul>
 <li>A total of 430 patients had established atherosclerotic cardiovascular disease.</li>
 <li>Among patients, 61.4% (n = 1,040) had a target LDL-C of ≤55 mg/dL and the rest (38.6%, n = 654) a target of ≤70 mg/dL</li>
 <li>Most treated patients were receiving a statin (97.5%) and about half were receiving additional ezetimibe (46.3%) and 4.9% were treated with a PCSK9i</li>
 </ul></li>
</ul>
<ul>
 <li>On-treatment LDL-C was 130 ± 49 mg/dL (3.4 ± 1.3 mmol/L). Almost half of patients (47.3%) had an LDL-C reduction &gt;50% than baseline. 
 <ul>
 <li>When 2019 ESC/EAS guidelines were applied to an FH cohort, the LDL-C goals achievement was only 2.7%</li>
 <li>In sub-group of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, only 2.2% and 3.6% achieved target, respectively (P = 0.146 between groups)</li>
 </ul></li>
 <li>After theoretical optimization of therapy to rosuvastatin/ezetimibe 40/10 mg daily, mean LDL-C level was 90 ± 26 mg/dL (2.3 ± 0.7 mmol/L). 
 <ul>
 <li>Increase of ESC/EAS 2019 target achievement rate was 5.9%</li>
 <li>In sub-group of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, 3.0% and 10.8% achieved target, respectively (P &lt;0.001 between groups)</li>
 <li>Significant percentage of patients (55.9%) would be eligible for PCSK9i treatment despite receiving rosuvastatin/ezetimibe 40/10 mg</li>
 </ul></li>
 <li>After theoretical administration of rosuvastatin/ezetimibe 40/10 mg plus PCSK9i (for those who were eligible): 
 <ul>
 <li>LDL-C target achievement rate would rise to 57.6%</li>
 <li>However, 42.4% of patients would still be eligible for further LDL-C lowering treatment</li>
 <li>In sub-group analysis of patients with LDL-C targets of ≤55 mg/dL and ≤70 mg/dL, 86.3% and 10.8% achieved target, respectively (P &lt; 0.001 between groups)</li>
 </ul></li>
 <li>In subgroup of patients (n = 337) with DLCN score ≥9 (i.e., definitive diagnosis of FH). 
 <ul>
 <li>Untreated LDL-C levels were 310 ± 90 mg/dL (8.0 ± 2.3 mmol/L)</li>
 <li>Among patients already on treatment (n = 266), mean LDL-C was 147 ± 60 mg/dL (3.8 ± 1.6 mmol/L) with only 2.6% patients achieving the 2019 ESC/EAS LDL-C target</li>
 <li>On switching all these patients not reaching LDL-C target as well as untreated patients to rosuvastatin/ezetimibe 40/10 mg, mean LDL-C was 112 ± 33 mg/dL (2.9 ± 0.9 mmol/L) and 3.3% patients reached target 
 <ul>
 <li>60.2% of patients with definite FH would be eligible for PCSK9i therapy despite receiving rosuvastatin/ezetimibe 40/10 mg versus 55.9% in the whole population.</li>
 </ul></li>
 </ul></li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Diagnosis of FH was made using the DLCN criteria.</li>
 <li>
 Participating sites were specialist outpatient lipid clinics.</li>
</ul>

Reference

LDL-C Targets in Patients with Heterozygous Familial Hypercholesterolemia

DYSLIPIDEMIA

CARDIOLOGY

<h2>Effectiveness and safety of PCSK9 inhibitors in Czech real-world practice.</h2>
Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) were effective and well-tolerated, with sustained effects, comparable to those in randomized studies.

<h2>Key Takeaway</h2>
<ul>
 <li>PCSK9i were effective in statin-intolerant patients, as significantly lower levels of low-density lipoprotein-cholesterol (LDL-C) were seen within 12 weeks.</li>
 <li>Target LDL-C levels were attained by 35.9% of patients in primary atherosclerotic cardiovascular disease (ASCVD) prevention and 65.7% of those in secondary ASCVD prevention at 1 year after therapy initiation.</li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>In patients with ASCVD with insufficient response or intolerant to traditional LDL-C-lowering therapies, PCSK9i can be beneficial.</li>
 <li>The extent to which the outcomes of therapy with PCSK9i in Czech real-world practice was comparable with those reported by large, randomized studies involving Czech patients was unknown.</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>The effect of PCSK9i therapy was assessed in the entire study population (N = 314; men = 44%; mean age = 63 years) in a Prague-based center of preventive cardiology between 31 July 2018 and 30 September 2020, including in the following subgroups of patients: 
 <ul>
 <li>With familial hypercholesterolemia (FH, 65%) vs. without FH, with LDL-C levels ≥4 mmol/L despite maximum tolerated dose (MTD) of statin 
 <ul>
 <li>Ezetimibe was given as an add-on, except if LDL-C levels were &gt;50% than target if statin-naïve, or &gt;20% if on statin at MTD</li>
 </ul></li>
 <li>With FH in primary (69%) or secondary (31%) ASCVD prevention, with LDL-C levels ≥3 mmol/L, despite lipid-lowering therapy at MTD 
 <ul>
 <li>Without FH in secondary ASCVD prevention (n = 107)</li>
 </ul></li>
 <li>On PCSK9i monotherapy alone vs. PCSK9i in combination with a statin</li>
 </ul></li>
 <li>Potential differences in the effect and tolerability of alirocumab (75 mg or 150 mg; n = 113) and evolocumab (140 mg; n = 156) were also assessed.</li>
 <li>Primary endpoints: Change in LDL-C, total cholesterol (TC), lipoprotein (a) Lp(a), apolipoprotein B (apoB), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (Tg) at 12 and 24 weeks, and 1 and 2 years after initiation of therapy with PCSK9i</li>
 <li>Secondary endpoints: Impact on glucose metabolism</li>
</ul>

<h2>Key Results</h2>
Effect on lipid parameters
<ul>
 <li>Changes in LDL-C levels: There was a significant reduction at 12 weeks (−59.4%) that continued to persist at 2 years (−62.6%)</li>
 <li>Changes in TC levels: There was a significant reduction at 12 weeks (decrease by 41.7%) and at 2 years (decrease by 43.9%)</li>
 <li>Changes in Lp(a) levels: There was a reduction at 12 weeks (−25.4%) and a further reduction at 24 weeks (−35.5%)</li>
 <li>Changes in apoB levels: There was a significant reduction at 12 weeks (54.2%) and at 2 years (58.1%)</li>
 <li>Changes in HDL-C levels: There was a slight increase at 12 weeks (4%) and at 2 years (5.6%)</li>
 <li>Changes in Tg levels: There was a significant reduction at 2 years (−30.3%), with levels reaching targets set by the 2019 ESC/EAS guidelines</li>
</ul>
Effect on glucose parameters
<ul>
 <li>Glucose metabolism was not affected by PCSK9i therapy</li>
</ul>
Effect on patients with and without FH
<ul>
 <li>Dynamics of decrease after therapy initiation were similar, with a decrease in LDL-C levels by 56.7% and 61.8% at 12 and 24 weeks in patients with FH compared to 67.4% and 68.8% in patients without FH, respectively</li>
 <li>At 2 years, significantly lower LDL-C levels were observed in both patients with FH (−63.5%) and those without FH (−62.3%)</li>
</ul>
Effect on patients with primary and secondary ASCVD prevention
<ul>
 <li>Dynamics of decrease after therapy initiation were similar, with a decrease in LDL-C levels by 55.7% and 61.5% at 12 and 24 weeks in patients in primary prevention, and by 63.9% and 66.3% in those in secondary prevention</li>
 <li>At 2 years, significantly lower LDL-C levels were observed in both patients in primary (−61.7%) and secondary (−64.2%) prevention</li>
</ul>
Effect on patients tolerant vs intolerant to statins
<ul>
 <li>By week 12, LDL-C levels in patients on maximum statin dose decreased by 65.2% compared to 55% in those not on statin therapy</li>
 <li>At 2 years, significant differences in LDL-C levels were seen between patients on maximum statin dose vs those who were statin-intolerant (64% vs 59.3%)</li>
</ul>
Effect on patients treated with alirocumab vs evolocumab
<ul>
 <li>By week 12, LDL-C levels in patients on alirocumab decreased by 55.5% compared to 66.1% in patients on evolocumab</li>
 <li>At 2 years, significant differences in LDL-C levels were seen (64.7% vs 61%) Correlation between baseline LDL-C levels and their decrease relative to therapy</li>
</ul>
Correlation between baseline LDL-C levels and their decrease relative to therapy
<ul>
 <li>Moderately strong inverse correlation (Pearson’s r = −0.7147) was seen</li>
</ul>
Effect on safety
<ul>
 <li>Side effects were reported by 9% of patients (alirocumab-related: 14; evolocumab-related: 16); 15 patients withdrew due to side effects</li>
 <li>Flu-like syndrome was more frequent (n = 13), followed by pain at injection site (n = 5), myalgia (n = 5), and gastrointestinal intolerance (n = 3)</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Patients were enrolled only from a single center and those not meeting the reimbursement criteria and self-payers were not included.</li>
 <li>Cardiovascular effects of PCSK9i were not assessed</li>
 <li>Patients were enrolled only if diagnosed with FH or statin intolerance, two indications for which reimbursement for treatment is permitted.</li>
</ul>

PCSK9 Inhibitors in Real World Practice

<h2>Incident heart failure tied to increased long-term risk for venous thromboembolism</h2>
Findings suggest the need for evidence-based strategies to prevent long-term venous thromboembolism in these patients beyond hospitalisation time.

<h2>Main Takeaway</h2>
<ul>
 <li>Incident heart failure (HF) hospitalisation was associated with more than a 3-fold higher risk for venous thromboembolism (VTE) which persisted through a long-term follow-up.</li>
 <li>The increased risk for VTE persisted in participants with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).</li>
 <li>In participants without clinical HF, left ventricular (LV) relative wall thickness and mean wall thickness were predictors of VTE.</li>
</ul>
<h2>Why This Matters</h2>
<ul>
 <li>HF not only increases the risk for cardioembolic events and ischaemic stroke but also increases the risk for VTE.</li>
 <li>Hospitalised patients for acute HF are at an increased risk for short-term VTE due to prolonged immobilisation and hypercoagulability</li>
</ul>
<h2>Study Design</h2>
<ul>
 <li>This prospective population-based study included 13,728 participants from the Atherosclerosis Risk In Communities (ARIC) cohort.</li>
 <li>Patients with (mean age, 56.1 years) and without (mean age, 53.5 years) incident HF hospitalisation were included.</li>
 <li>Short- and long-term VTE risks associated with: 
 <ul>
 <li>incident HF during 1987-2015 (n=13,728; design 1);</li>
 <li>HF subtype during 2005-2015 (n=7588; design 2); and</li>
 <li>abnormal echocardiographic measures in the absence of clinical HF during 2011-2015 (n=5438; design 3) were assessed.</li>
 </ul></li>
 <li>Funding: ARIC cohort was funded by the National Heart, Lung, and Blood Institute.</li>
</ul>

<h2>Key Results</h2>
<ul>
 <li>Incident HF occurred in 19.6% of patients included in the design1.</li>
 <li>During a mean follow-up of 22±7 years, incident HF vs no HF was associated with an increased risk for incident total VTE (adjusted HR [aHR], 3.13; 95% CI, 2.58-3.80).</li>
 <li>Incident HF vs no HF was associated with a 2-fold greater risk for all VTE subtypes: 
 <ul>
 <li>Pulmonary embolism: aHR, 2.57; 95% CI, 1.95-3.39;</li>
 <li>Deep venous thrombosis: aHR, 3.90; 95% CI, 2.96-5.13;</li>
 <li>Provoked VTE events: aHR, 2.26; 95% CI, 1.60-3.19; and</li>
 <li>Unprovoked VTE events: aHR, 3.72; 95% CI, 2.94-4.72.</li>
 </ul></li>
 <li>Incident HF occurred in 15.3% of participants allocated to the design2.</li>
 <li>Over a mean follow-up of 9.7±2.6 years, VTE rates in those with vs without HF were 21.8 (95% CI, 16.9-27.6) vs 3.04 (95% CI, 2.64-3.49) per 1000 person-years.</li>
 <li>Compared with no HF, VTE risk was reported in: 
 <ul>
 <li>Any HF: aHR, 5.15; 95% CI, 3.80-6.98;</li>
 <li>HFpEF: aHR, 4.71; 95% CI, 2.94-7.52;</li>
 <li>HFrEF: aHR, 5.53; 95% CI, 3.42-8.94; and</li>
 <li>Undetermined incident HF: aHR, 4.09; 95% CI, 2.60-6.44.</li>
 </ul></li>
 <li>In participants allocated to the design 3, 86 incident VTE events were reported over a mean follow-up of 3.5±0.7 years.</li>
 <li>In the absence of baseline HF, LV relative wall thickness (P=0.002) and mean LV wall thickness (P=0.003) were found to be predictors of incident VTE after additional adjustment for chronic kidney disease and atrial fibrillation</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>ARIC-based incident HF on hospitalisations.</li>
 <li>VTE validation failed to capture outpatient VTE.</li>
 <li>The number of VTE events for design 3 was small.</li>
 <li>The observed association between HF and VTE may not be causal.</li>
 <li>Incident VTE-related mortality was not assessed.</li>
</ul>

Incident heart failure tied to increased long-term risk for VTE

THROMBOSIS

PAD is a common manifestation of atherosclerosis and encompasses all vascular sites, including:1
<ul>
 <li>
 Lower extremity arteries</li>
 <li>
 Carotid artery</li>
 <li>
 Vertebral artery</li>
 <li>
 Upper extremity arteries</li>
 <li>
 Mesenteric artery</li>
 <li>
 Renal artery</li>
 <li>
 Aorta</li>
</ul>
New 2024 ESC&nbsp;guidelines for the management of peripheral arterial and aortic diseases (PAAD) show:2

Increased risk of CV events in patients with PAD compared with those without PAD2

Patients with both PAD and T2DM are at a ‘very high’ risk of cardiovascular events2

In a prospective cohort study in Europe, patients with PAD and T2DM had...

Higher risk of CV events* compared to those with neither PAD nor T2DM3

Screening for lower-extremity arterial disease (LEAD) is recommended on a regular basis, with clinical assessment and/or ankle-brachial index (ABI) measurement.2,4

Adapted from Marx N et al. 2023 and Mazzolai L et al. 2024.2,4
a&nbsp;TBI when ABI &gt;1.4. b&nbsp;Further information regarding wound management and exercise training can be found in the 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases. c&nbsp;MRA or CTA when duplex sonography is not sufficient for planning revascularisation.

Patients with PAD,&nbsp;with or without T2DM, are at very&nbsp;high CV risk.1 
 These patients require a&nbsp;holistic multifactorial approach&nbsp;to prevention and management.
Reduce increased levels of causal CV risk factors, such as:1

Target: see below

Target: SBP 120–129 mmHg†

Target is &lt;7.0% (53 mmol/mol)

Reducing LDL-C levels represents the primary target for reducing CV risk1
According to the 2019 ESC/EAS dyslipidaemia guidelines, and 2024 ESC chronic coronary syndromes guidelines, all patients with PAD have the following LDL-C goals.1,2
An LDL-C reduction of ≥50% from baseline‡&nbsp;and an&nbsp;LDL-C goal of &lt;55 mg/dL (&lt;1.4 mmol/L)&nbsp;are recommended
For patients at&nbsp;very high CV risk&nbsp;(including those with PAD and T2DM) not achieving their LDL-C goal on a maximum tolerated dose of statin and ezetimibe, combination&nbsp;with a PCSK9i is recommended.1

Recommendations for pharmacological LDL-C lowering1

It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the specific level of risk.

Step 1

If the goals are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended.

Step 2

For secondary prevention, patients at very high risk not achieving their goal on a maximum tolerated dose of a statin and ezetimibe, combination with a PCSK9i is recommended.

Step 3

Adapted from Mach F et al. 2019 and Mazzolai L et al. 2024.1,2

You should aim to assess your patients response to therapy&nbsp;6–8 weeks from initiation.1

Prevent The 1st&nbsp;Event&nbsp;for your 
 patients with&nbsp;PAD + T2DM¥
*When compared to those with neither PAD nor T2DM, HRs adjusted for age, gender, BMI, smoking, hypertension, LDL-C, and HDL-C were 1.26 (95% Cl 0.84, 1.91); P=0.267, HR 4.17 (95% Cl 2.97, 5.85); P&lt;0.001, and HR 7.82 (95% Cl 5.49, 11.12); P&lt;0.001 for those with T2DM only, for those with PAD only and for those with the combination of PAD plus T2DM, respectively.3
†Provided the antihypertensive treatment is well tolerated.
‡The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C-lowering medication. In people who are taking LDL-C-lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-lowering efficacy of the given medication or combination of medications.1
¥Prevent the first major CV event for your ASCVD patients without prior major CV event.
In a prospective cohort study, cardiovascular events were prospectively recorded over a mean follow-up period of 7.2 ± 2.6 years in 1,049 subjects, encompassing 4 groups: 558 with neither PAD nor diabetes, 153 with T2DM but without PAD, 192 with PAD but without T2DM, and 146 with the combination of PAD and T2DM. 4 PAD patients were defined as those with an ankle brachial index &lt;0.9 or with previous revascularisation of peripheral arteries who underwent routine duplex sonography and in whom PAD was sonographically verified.3
ABI&nbsp;=&nbsp;ankle–brachial index;&nbsp;ASCVD&nbsp;= atherosclerotic cardiovascular disease;&nbsp;BMI&nbsp;= body mass index;&nbsp;CI&nbsp;= confidence interval;&nbsp;CTA&nbsp;= computed tomography angiography;&nbsp;CV&nbsp;= cardiovascular;&nbsp;EAS&nbsp;= European Atherosclerosis Society;&nbsp;ESC&nbsp;= European Society of Cardiology;&nbsp;HbA1c&nbsp;= glycated haemoglobin;&nbsp;HDL-C&nbsp;= high-density lipoprotein cholesterol;&nbsp;HR&nbsp;= hazard ratio;&nbsp;LEAD&nbsp;= lower- extremity artery disease;&nbsp;LDL-C&nbsp;= low-density lipoprotein cholesterol;&nbsp;MRA&nbsp;= magnetic resonance angiography;&nbsp;PAAD&nbsp;= peripheral arterial and aortic disease;&nbsp;PAD&nbsp;= peripheral artery disease;&nbsp;PCSK9i&nbsp;= proprotein convertase subtilisin/kexin type 9 inhibitor;&nbsp;SBP&nbsp;= systolic blood pressure;&nbsp;TBI&nbsp;= toe-brachial index;&nbsp;TcPO2&nbsp;= transcutaneous oxygen pressure;&nbsp;T2DM&nbsp;= type 2 diabetes mellitus;&nbsp;WlfI&nbsp;= Wound, Ischaemia, foot Infection.

References

Approach for Patients with PAD and T2D: Focus on LDL-C Control

CAD is defined as the pathological process characterised by atherosclerotic plaque accumulation in the epicardial arteries. It covers different conditions, including:1
<ul>
 <li>Patients with stable angina</li>
 <li>Patients after elective coronary revascularisation procedures, such as percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)</li>
 <li>Patients with significant coronary disease without prior revascularisation as evidenced by either: 
 <ul>
 <li>≥70% stenosis of at least one coronary artery</li>
 <li>≥50% stenosis of the left main coronary artery</li>
 <li>Three-vessel obstructive (&gt;70%) disease</li>
 </ul></li>
</ul>

Ischaemic heart disease accounts for 16% of all deaths worldwide.2*

The presence of T2DM alongside CAD was shown to increase the risk of a CV event by 28% vs those without diabetes in the CLARIFY study.3 
 Diabetes is a well-established risk factor for ischaemic heart disease, and CAD accounts for 40–80% of deaths in patients with T2DM.1

New 2024 ESC guidelines for the management of chronic coronary syndromes have been published recently and can be downloaded by clicking the button

These guidelines present the following steps for management of chronic coronary syndrome (CCS), including CAD4

Adapted from 2024 ESC CCS Guidelines.4
a&nbsp;High–risk CAD: obstructive CAD at high risk of adverse events by CCTA: ≥50% stenosis of the left main stem; three–vessel disease with severe stenoses (≥70% diameter stenosis); single- or two– vessel disease including the proximal LAD with severe stenoses. Consider functional imaging or invasive investigation.
Patients with CAD, with or without T2DM, are at&nbsp;very high CV risk.5&nbsp;These patients require a&nbsp;holistic multifactorial approach&nbsp;to prevention and management.

Patients with PAD,&nbsp;with or without T2DM, are at very&nbsp;high CV risk.1 
 These patients require a&nbsp;holistic multifactorial approach&nbsp;to prevention and management.
Reduce increased levels of causal CV risk factors, such as:5

Reducing LDL-C levels represents the primary target for reducing CV risk5
According to the 2019 ESC/EAS dyslipidemia guidelines, and 2024 ESC chronic coronary syndromes guidelines, all patients with CAD have the following LDL-C goals.4,5
An LDL-C reduction of ≥50% from baseline‡&nbsp;and an&nbsp;LDL-C goal of &lt;55 mg/dL (&lt;1.4 mmol/L)&nbsp;are recommended
For patients at&nbsp;very high CV risk&nbsp;(including those with CAD) not achieving their LDL-C goal on a maximum tolerated dose of statin and ezetimibe, combination&nbsp;with a PCSK9i is recommended.5

Recommendations for pharmacological LDL-C lowering5

Adapted from Vrints et al. 2024 and Mach et al. 20204,5

You should aim to assess your patients response to therapy&nbsp;6–8 weeks from initiation.5

Prevent The 1st&nbsp;Event&nbsp;for your CAD&nbsp;patients with&nbsp;PAD + T2DM¥
*The term stable ischaemic heart disease often is used synonymously with chronic CAD and encompasses a variety of conditions that result in a mismatch between myocardial oxygen supply and demand.6
†Provided the antihypertensive treatment is well tolerated.
‡The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C-lowering medication. In people who are taking LDL-C-lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based on the average LDL-C-lowering efficacy of the given medication or combination of medications.5
¥Prevent the first major CV event for your CAD and T2DM patients without prior major CV event. CLARIFY is an observational registry of patients with chronic coronary syndromes, taking place across 45 countries from 2009 to 2010; follow-up was 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis &gt;50%, proven symptomatic myocardial ischaemia, or prior revascularisation procedure.3
ANOCA&nbsp;= angina with non-obstructive coronary arteries;&nbsp;CABG&nbsp;= coronary artery bypass graft;&nbsp;CAD&nbsp;= coronary artery disease;&nbsp;CCS&nbsp;= chronic coronary syndromes;&nbsp;CCTA&nbsp;= coronary computed tomography angiography;&nbsp;CMR&nbsp;= cardiac magnetic resonance;&nbsp;CV&nbsp;= cardiovascular;&nbsp;EAS&nbsp;= European Atherosclerosis Society;&nbsp;ECHO&nbsp;= echocardiography;&nbsp;ESC&nbsp;= European Society of Cardiology;&nbsp;FFR&nbsp;= fractional flow reserve;&nbsp;HbA1c&nbsp;= glycated haemoglobin;&nbsp;ICFT&nbsp;= invasive coronary functional testing;&nbsp;iFR&nbsp;= instantaneous wave-free ratio;&nbsp;INOCA&nbsp;= ischaemia with non-obstructed coronary arteries;&nbsp;LAD&nbsp;= left anterior descending artery;&nbsp;LDL-C&nbsp;= low-density lipoprotein cholesterol;&nbsp;LV&nbsp;= left ventricular;&nbsp;PCI&nbsp;= percutaneous coronary intervention;&nbsp;PCSK9i&nbsp;= proprotein convertase subtilisin/kexin type 9 inhibitor;&nbsp;PET&nbsp;= positron emission tomography;&nbsp;SBP&nbsp;= systolic blood pressure;&nbsp;SPECT&nbsp;= single-photon emission computed tomography;&nbsp;T2DM&nbsp;= type 2 diabetes mellitus.

Approach for Patients with CAD: Focus on LDL-C Control

Cardiovascular disease (CVD) is responsible for &gt;4 million deaths in Europe each year. The 2019 ESC/EAS Guidelines for the management of dyslipidaemias define those with documented ASCVD, type 1 or type 2 diabetes mellitus, very high levels of individual risk factors, or chronic kidney disease (CKD) as&nbsp;very-high CV risk.1

In very-high CV risk patients, the 2019 ESC/EAS dyslipidaemia guidelines recommend:1

These patients require pharmacological intervention alongside lifestyle management to help reach targets.1
Intensity of lipid lowering treatment
<table border="1" cellpadding="1" cellspacing="1">
 <tbody>
 <tr>
 <td style="background-color: rgb(54, 145, 255);">
 Treatment</td>
 <td style="background-color: rgb(54, 145, 255);">
 Average LDL-C reduction</td>
 </tr>
 <tr>
 <td>
 Moderate intensity statin</td>
 <td>
 ≈ 30%</td>
 </tr>
 <tr>
 <td>
 High intensity statin</td>
 <td>
 ≈ 50%</td>
 </tr>
 <tr>
 <td>
 High intensity statin plus ezetimibe</td>
 <td>
 ≈ 65%</td>
 </tr>
 <tr>
 <td>
 PCSK9 inhibitor</td>
 <td>
 ≈ 60%</td>
 </tr>
 <tr>
 <td>
 PCSK9 inhibitor plus high intensity statin</td>
 <td>
 ≈ 75%</td>
 </tr>
 <tr>
 <td>
 PCSK9 inhibitor plus high intensity statin plus ezetimibe</td>
 <td>
 ≈ 85%</td>
 </tr>
 </tbody>
</table>
Adapted from ESC/EAS Guidelines for the management of dyslipidaemias. 2019.1 
 No direct comparisons can be made between the above treatments due to the absence of head to head data.

The 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes outline the same underlying principles for the management of dyslipidaemia, with the addition of more specific guidelines for patients with diabetes. Very-high CV risk patients with diabetes are also recommended an LDL-C reduction of ≥50% and an LDL-C goal of &lt;55 mg/dL (&lt;1.4 mmol/L).2
CV risk assessment and treatment targets 
 All T2DM patients with established ASCVD are considered very-high risk.2 
 In patients aged ≥40 years with T2DM without ASCVD or severe TOD, it is recommended to estimate 10-year CVD risk using the SCORE2-Diabetes algorithm.

Adapted from ESC Guidelines for the management of cardiovascular disease in patients with diabetes. 2023.2 LDL-C management algorithm for patients with diabetes2
Level of recommendations:

High intensity statins are recommended as the first-choice LDL-C-lowering treatment in patients with diabetes and above target LDL-C levels.

black

If the target LDL-C is not reached with statins, combination therapy with ezetimibe is recommended.

A PCSK9 inhibitor is recommended in patients at very high CV risk, with persistently high LDL-C levels above target despite treatment with a MTD statin + ezetimibe, or in patients with statin intolerance.

*Severe TOD defined as eGFR &lt;45 mL/min/1.73m2 irrespective of albuminuria; or eGFR 45–59 mL/ min/1.73m2 and microalbuminuria (UACR 30–300 mg/g; stage A2); or proteinuria (UACR &gt;300 mg/g; stage A3), or presence of microvascular disease in at least three different sites [e.g. microalbuminuria (stage A2) plus retinopathy plus neuropathy].2
†The thresholds (10-year CVD risk) suggested are not definitive but rather designed to prompt joint decision-making conversations with patients about intensity of treatment, as well as additional interventions. SCORE2-Diabetes refers to patients aged ≥40 years.2
ASCVD&nbsp;= atherosclerotic cardiovascular disease;&nbsp;CV&nbsp;= cardiovascular;&nbsp;CVD&nbsp;= cardiovascular disease;&nbsp;EAS&nbsp;= European Atherosclerosis Society; eGFR&nbsp;= estimated glomerular filtration rate;&nbsp;ESC&nbsp;= European Society of Cardiology;&nbsp;LDL-C&nbsp;= low-density lipoprotein cholesterol;&nbsp;MTD&nbsp;= maximum tolerated dose;&nbsp;PCSK9&nbsp;= proprotein convertase subtilisin kexin type 9;&nbsp;T2DM&nbsp;= type 2 diabetes mellitus;&nbsp;TOD&nbsp;= target organ damage;&nbsp;UACR&nbsp;= urine albumin-to-creatinine ratio

Lipid Management in Patients with Diabetes Mellitus

A meta-analysis of observational studies and randomized controlled trials on the relationship between low-density lipoprotein cholesterol and lipid-lowering agents and the risk of stroke.
The findings from this systematic review and meta-analysis can be useful to identify the optimal low-density lipoprotein cholesterol (LDL-C) range to prevent the risk of stroke and plan future studies with different LDL-C targets and lipid-lowering agents (LLAs).

<h2>Key Takeaway</h2>
This systematic review and meta-analysis evaluating the impact of LDL-C levels from cohort studies and LLAs from randomized controlled trials (RCTs) on the risk of different types of strokes demonstrated:
<ul>
 <li>Non-significant trend towards a higher risk of hemorrhagic stroke for all investigated LDL-C levels.</li>
 <li>Significantly higher risk of ischemic stroke with higher LDL-C levels (&gt;70 mg/dL).</li>
 <li>Large effect on all strokes and ischemic strokes, but no significant effect on hemorrhagic strokes by statin and non-statin LLAs.</li>
</ul>
Overall, the data did not show any significant association between LDL-C thresholds and different LLAs and the risk of hemorrhagic stroke.
<ul>
 <li>However, most effects seen in the present analysis were subject to high levels of heterogeneity.</li>
 <li>Thus, well-designed studies are still warranted to determine the effects of low to extremely low LDL-C levels on hemorrhagic stroke and the role of LLAs.</li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>The effects of dyslipidemia on the pathogenesis of stroke are less clear and the relationship between cholesterol and ischemic stroke is inconsistent.</li>
 <li>The impact of LLAs on stroke types has also not been well established.</li>
 <li>Due to the paucity of studies and conflicting findings, this meta-analysis was conducted to better understand the relationship between low LDL-C levels and various types of strokes based on findings from observational studies and the impact of LLAs and risk of different types of strokes based on RCTs.</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>Prospective cohort studies and RCTs† published up to 1 September 2019 were searched using PubMed, Embase, and Scopus databases.</li>
 <li>The primary exposure of interest for cohort studies was LDL-C level and primary outcomes were different types of strokes.</li>
 <li>The primary outcome of RCTs was stroke</li>
 <li>Meta-analyses were performed by levels of achieved LDL-C (≤1.3 mmol/L, 1.3 to &lt;1.8 mmol/L, and ≥1.8 mmol/L), statin or non-statin groups, primary vs secondary prevention, and specific type of stroke—ischemic and hemorrhagic.</li>
</ul>

<h2>Key Results</h2>
Cohort studies:
Characteristics of included cohort studies:
<ul>
 <li>Eleven cohort studies involving 355,591 patients with 11,888 events were included in the meta-analysis</li>
 <li>All studies included both sexes and the mean follow-up duration was 9.9 years (range: 4.9–19 years)</li>
</ul>
Association between LDL-C levels and stroke observed in cohort studies:
<ul>
 <li>The highest LDL-C quartile was not associated with stroke events vs the lowest LDL-C quartile (hazard ratio [HR] = 1.032; P = 0.412; n = 3 studies; I2&nbsp;= 0%).</li>
 <li>Patients in the highest LDL-C quartile had a lower risk of hemorrhagic strokes (HR = 0.913; P = 0.012; n = 7 studies; I2 = 0%) and a higher risk of ischemic stroke (HR = 1.105; P &lt;0.001; n = 7 studies; I2&nbsp;= 0%).</li>
 <li>No significant association was seen between LDL-C and intracerebral hemorrhage events (HR = 0.99; P = 1.0; n = 2 studies; I2&nbsp;= 0%).</li>
 <li>Sensitivity analysis: Pooled effect estimates were similar for the association between LDL-C and hemorrhagic stroke (HR = 0.91) and LDL-C and ischemic stroke (HR = 1.10).</li>
</ul>
RCTs:
Characteristics of included RCTs:
<ul>
 <li>Eighteen RCTs published between 2002 and 2018 involving 165,988 patients were included in the meta-analysis</li>
 <li>Across studies, the number of patients ranged from 2,107 to 27,564 and the proportion of men ranged from 48.3–82.2%, with a mean age of 63.1 years</li>
 <li>The mean follow-up duration from baseline to endpoint was 4.1 years</li>
 <li>The baseline and achieved LDL-C levels were 2.25–4.1 mmol/L and 0.78–3.1 mmol/L, respectively</li>
</ul>

<table align="center" border="1" cellpadding="10" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td colspan="4" rowspan="1" style="background-color: rgb(244, 242, 246); text-align: center; width: 50%;">LDL-C levels achieved</td>
 <td colspan="2" rowspan="1" style="background-color: rgb(244, 242, 246); width: 25%;">Statin vs non-statin/ 
 combination therapy</td>
 <td colspan="2" rowspan="1" style="background-color: rgb(244, 242, 246); width: 25%;">Primary vs secondary prevention</td>
 </tr>
 <tr>
 <td style="width: 50%;">Effect of LLAs</td>
 <td style="width: 50%;">&nbsp;≤ 1.3 mmol/L</td>
 <td style="width: 50%;">1.3 &nbsp;≤ 1.8 mmol/L</td>
 <td style="width: 50%;">≥1.8 mmol/L</td>
 <td style="width: 25%;">Statin</td>
 <td style="width: 25%;">Non-statin</td>
 <td style="width: 25%;">Primary</td>
 <td style="width: 25%;">Secondary</td>
 </tr>
 <tr>
 <td style="width: 50%;">All strokes&nbsp;</td>
 <td style="width: 50%;">RR = 0.81 
 p &lt; 0.001 
 I2&nbsp;= 27% 
 n = 3</td>
 <td style="width: 50%;">RR = 0.83 
 p = 0.299 
 I2&nbsp;= 72% 
 n = 3</td>
 <td style="width: 50%;">RR = 0.88 
 p = 0.008 
 I2&nbsp;= 53% 
 n = 13</td>
 <td style="width: 25%;">RR = 0.82 
 p = 0.011 
 I2&nbsp;= 56% 
 n = 15</td>
 <td style="width: 25%;">RR = 0.81 
 p &lt; 0.001 
 I2&nbsp;= 0.0% 
 n = 4</td>
 <td style="width: 25%;">RR = 0.854 
 p &lt; 0.001 
 I2&nbsp;= 52.7% 
 n = 17</td>
 <td style="width: 25%;">RR = 0.90 
 p = 0.092 
 I2&nbsp;= 24.5% 
 n = 2</td>
 </tr>
 <tr>
 <td style="width: 50%;">Ischemic Strokes</td>
 <td style="width: 50%;">RR = 0.78 
 I2&nbsp;= 0.0% 
 n = 3</td>
 <td style="width: 50%;">RR = 0.76 
 p = 0.104 
 I2&nbsp;= 56.7% 
 n = 3</td>
 <td style="width: 50%;">RR = 0.75 
 p &lt; 0.001 
 I2&nbsp;= 0.0% 
 n = 4</td>
 <td style="width: 25%;">
 RR = 0.76 I2&nbsp;= 32% 
 p &lt; 0.001 
 n = 6</td>
 <td style="width: 25%;">RR = 0.77 
 p &lt; 0.001 
 I2&nbsp;= 0.0% 
 n = 4</td>
 <td style="width: 25%;">-</td>
 <td style="width: 25%;">-</td>
 </tr>
 <tr>
 <td style="width: 50%;">Hemorrhagic strokes‡</td>
 <td style="width: 50%;">RR = 1.14 
 I2&nbsp;= 43.6%&nbsp; 
 n = 3</td>
 <td style="width: 50%;">RR = 1.20 
 p = 0.301 
 I2&nbsp;= 0.0% 
 n = 2</td>
 <td style="width: 50%;">RR = 1.25 
 p = 0.289 
 I2&nbsp;= 57.9% 
 n = 5</td>
 <td style="width: 25%;">RR = 1.23&nbsp; 
 p = 0.219 
 I2&nbsp;= 47.4% 
 n = 6</td>
 <td style="width: 25%;">RR = 1.16 
 p = 0.232 
 I2&nbsp;= 16.5% 
 n = 4</td>
 <td style="width: 25%;">-</td>
 <td style="width: 25%;">-</td>
 </tr>
 </tbody>
</table>

Abbreviations

<h2>Limitations</h2>
<ul>
 <li>Relatively high heterogeneity was observed in the link between LDL levels and stroke and between studies.</li>
 <li>There was no sufficient statistical power and low level of type I and II error for RCTs on hemorrhagic stroke.</li>
</ul>
*For additional details and inclusion and exclusion criteria for cohort studies/RCTs, please refer to the source publication Banach M, et al. †RCTs were also searched on Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science by Clarivate and www.clinicaltrials.gov register. ‡Statin therapy was compared with combination therapy

Relationship Between LDL-C LLTs and Risk of Stroke

<h2>Key Takeaway</h2>
This simulation study&nbsp;from Da Vinci&nbsp;identified notable differences&nbsp;between the&nbsp;2019 ESC/EAS&nbsp;and&nbsp;2018 ACC/AHA&nbsp;guidelines in their&nbsp;clinical approach to LLT in patients with ASCVD. The study also identified that:
<ul>
 <li>About&nbsp;80–85%&nbsp;of the patients* were on&nbsp;monotherapy based LLT</li>
 <li>Patients&nbsp;achieving 2018 ACC/AHA&nbsp;(&lt;70 mg/dL) vs&nbsp;2019 ESC/EAS&nbsp;(&lt;55 mg/dL) goals were&nbsp;39% vs 19%</li>
 <li>Achievement&nbsp;of&nbsp;LDL−C&nbsp;&lt;70 mg/dL&nbsp;was&nbsp;more likely in patients&nbsp;receiving&nbsp;combination therapy&nbsp;with either&nbsp;ezetimibe&nbsp;or a&nbsp;PCSK9i&nbsp;vs patients on statin monotherapy</li>
 <li>In patients&nbsp;with&nbsp;LDL−C ≥70 mg/dL, to achieve LDL−C levels of&nbsp;&lt;70 mg/dL, &lt;55 mg/dL&nbsp;and&nbsp;&lt;40 mg/dL, median LDL−C reductions&nbsp;of&nbsp;26%,&nbsp;42%&nbsp;and&nbsp;58%&nbsp;would be needed, respectively</li>
 <li>In patients with&nbsp;LDL–C ≥70 mg/dL&nbsp;vs&nbsp;&lt;70 mg/dL, the estimated&nbsp;10–year risk of CV events&nbsp;were&nbsp;32% vs 35%</li>
 <li>Attaining&nbsp;2018 ACC/AHA or 2019 ESC/EAS goals resulted in&nbsp;simulated ARRs&nbsp;of&nbsp;4%&nbsp;and&nbsp;6%, respectively</li>
 <li>For&nbsp;implementation of the guidelines,&nbsp;greater use&nbsp;of&nbsp;combination therapies&nbsp;would be required</li>
 <li>The&nbsp;residual risk&nbsp;among patients with ASCVD&nbsp;receiving statins&nbsp;could be&nbsp;mitigated&nbsp;if&nbsp;2019 ESC/EAS recommendations&nbsp;were&nbsp;achieved‡</li>
 <li>More stringent 2019 ESC/EAS goals&nbsp;are&nbsp;expected&nbsp;to give&nbsp;better health&nbsp;outcomes&nbsp;vs 2018 ACC/AHA approach</li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>LDL–C recommendations differ between&nbsp;the 2018 ACC/AHA approach&nbsp;and&nbsp;2019 ESC/EAS guidelines&nbsp;for patients with&nbsp;ASCVD.</li>
 <li>The&nbsp;2018 ACC/AHA guidelines&nbsp;recommend targeted reduction&nbsp;LDL–C &lt;70 mg/dL§, in patients at&nbsp;very–high risk.</li>
 <li>The&nbsp;2019 ESC/EAS guidelines&nbsp;recommend a&nbsp;stricter LDL–C goal of &lt;55 mg/dL.</li>
 <li>Using&nbsp;DA VINCI study cohort, the&nbsp;extent of risk that could be mitigated by adopting 2018 ACC/AHA&nbsp;vs&nbsp;2019 ESC/EAS&nbsp;LDL−C recommended approaches was&nbsp;simulated.</li>
</ul>

<h2>Study Design</h2>
This is a simulation study from Da Vinci.&nbsp;The methods and primary outcomes of Da Vinci study can be obtained from the link:&nbsp;<a href="https://www.sciencedirect.com/science/article/pii/S0021915021013083">Da Vinci.</a>
<ul>
 <li>LLT use across the populations</li>
 <li>LDL–C control in patients with established ASCVD and stratified by ASCVD type¶</li>
 <li>Patients with LDL–C &gt;70 mg/dL vs achievement of LDL–C &lt;55 mg/dL</li>
 <li>Patients achieving LDL–C &lt;40 mg/dL</li>
 <li>Implications of current practice and LDL–C goal achievement in future CV risk</li>
</ul>

<h2>Key Results</h2>
Overall,&nbsp;2,039 patients with ASCVD&nbsp;(23% with CAD; 37% with CBD and 40% with PAD)&nbsp;were on stabilized LLT&nbsp;at the time of&nbsp;LDL–C measurement.

LLT Use in patients with ASCVD
<table border="1" cellpadding="10" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(244, 242, 246);">Type of&nbsp;LLT</td>
 <td style="background-color: rgb(244, 242, 246);">Patients using LLT (%)</td>
 </tr>
 <tr>
 <td>
 Statin monotherapy</td>
 <td>Used most frequently</td>
 </tr>
 <tr>
 <td>Moderate–intensity statins#&nbsp;as monotherapy</td>
 <td>Ranged from&nbsp;40.4%&nbsp;among patients with CAD to&nbsp;48.7%&nbsp;in patients with CBD</td>
 </tr>
 <tr>
 <td>High–intensity statins#</td>
 <td>CAD: 51.1%;&nbsp;CBD: 39.7%; PAD: 39.1%</td>
 </tr>
 <tr>
 <td>Ezetimibe in combination with statins||</td>
 <td>CAD: 15.3%;&nbsp;CBD: 6.7%; PAD: 8.2%</td>
 </tr>
 <tr>
 <td>PCSK9i in combination with statins and/or ezetimibe||</td>
 <td>CAD: 0.4%; CBD: 1.2%; PAD: 1.6%</td>
 </tr>
 </tbody>
</table>

Proportion of patients achieving LDL–C Levels

<ul>
 <li>Achievement of an&nbsp;LDL–C level &lt;70 mg/dL&nbsp;was&nbsp;more likely&nbsp;in patients receiving&nbsp;combination therapy with either ezetimibe or a PCSK9i&nbsp;vs patients on statin monotherapy.</li>
 <li>Despite of using PSCK9i infrequently,&nbsp;58% of patients receiving PSCK9i&nbsp;in combination with other LLT have&nbsp;attained LDL–C level of &lt;55 mg/dL.</li>
</ul>

Residual risk among the patients
<table border="1" cellpadding="10" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(244, 242, 246);">LDL–C Levels</td>
 <td style="background-color: rgb(244, 242, 246);">Patients&nbsp;(%)</td>
 <td style="background-color: rgb(244, 242, 246);">Median&nbsp;(IQR) LDL–C Level</td>
 <td style="background-color: rgb(244, 242, 246);">Median&nbsp;(IQR) Predicted&nbsp;10–year&nbsp;CV risk</td>
 </tr>
 <tr>
 <td>≥70 mg/dL</td>
 <td>61%</td>
 <td>93 (81–115) mg/dL</td>
 <td>32% (25–43%)</td>
 </tr>
 <tr>
 <td>&lt;70 mg/dL**</td>
 <td>39%</td>
 <td>56 (46–63) mg/dL</td>
 <td>35% (26–46%)</td>
 </tr>
 </tbody>
</table>
Simulated risk reduction in patients with established&nbsp;ASCVD (LDL–C Level of ≥70 mg/dL)
<table border="1" cellpadding="10" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="background-color: rgb(244, 242, 246);">LDL–C Levels</td>
 <td style="background-color: rgb(244, 242, 246);">Median&nbsp;10–year&nbsp;CV risk</td>
 <td style="background-color: rgb(244, 242, 246);">Median&nbsp;RRR of&nbsp;CV events</td>
 <td style="background-color: rgb(244, 242, 246);">Median&nbsp;ARR of CV events</td>
 <td style="background-color: rgb(244, 242, 246);">
 Required&nbsp; 
 median&nbsp; 
 reduction&nbsp;in&nbsp; 
 LDL-C</td>
 <td style="background-color: rgb(244, 242, 246);">AR to lower&nbsp;LDL–C levels&nbsp;to 69 mg/dL</td>
 </tr>
 <tr>
 <td>&lt;70 mg/dL</td>
 <td>28%</td>
 <td>14%</td>
 <td>4%</td>
 <td>26%</td>
 <td>24 mg/dL (12–46)</td>
 </tr>
 <tr>
 <td>&lt;55 mg/dL</td>
 <td>25%</td>
 <td>22%</td>
 <td>6%</td>
 <td>42%</td>
 <td>39 mg/dL (27–91)</td>
 </tr>
 <tr>
 <td>&lt;40 mg/dL</td>
 <td>23%</td>
 <td>29%</td>
 <td>8%</td>
 <td>58%</td>
 <td>54 mg/dL (42–76)</td>
 </tr>
 </tbody>
</table>
For additional information about simulated risk reduction, please click on the&nbsp;<a href="http://${link:{uuid:{e3579e13-0af7-4531-bdf0-88d2e3d87092},repository:{dam},path:{/Portal/KSA/Articles/recommendations-for-residual-risk-reduction-in-ascvd/STRATIFIED-BY-ASCVD-TYPE.pdf}}}">hyperlink.</a>

<h2>Limitations</h2>
<ul>
 <li>Over 90% of patients were white (homogenous ethnicity).</li>
 <li>Simulation might have underestimated CV risk and ARR in very high-risk patients.</li>
 <li>Use of LLT may vary across countries and might not necessarily reflect practice in other regions.</li>
 <li>The study sites might have focused on lipid management and prevention of CV events. Hence, the study findings are likely to present better than average management scenario.</li>
</ul>
For additional details, please refer the source publication&nbsp;<a href="https://link.springer.com/article/10.1007/s10557-022-07343-x#Abs1">Vallejo-Vaz AJ, et al.</a> 
 * Most of the patients with major manifestations of ASCVD 
 † Probably due to additional comorbidities like diabetes, history of smoking and increased use of more potent LLTs including combination therapies. 
 ‡ In a population like Da Vinci cohort § Using 70 mg/dL as a limit to guide additional LLT 
 ¶ As per 2019 ESC/EAS guidelines, all patients are at very–high risk 
 # With or without other LLT || High/moderate/unknown intensity 
 ** Had slightly higher prevalence of risk factors such as a history of smoking and diabetes (50.7%)

ACC/AHA vs ESC/EAS LDL–C recommendations for residual risk reduction in ASCVD: A simulation study from Da Vinci

Five-year update on ESC/EAS guidelines for detection, prevention, and treatment of individuals at risk of a first myocardial infarction*
When compared with 2016 and 2019 ESC/EAS (European Society of Cardiology/ European Atherosclerosis Society) guidelines, the 2021 ESC guidelines improved detection and treatment of men and women who are at risk for a first ST-segment elevated myocardial infraction (STEMI).

<h2>Key Takeaway</h2>
This study aimed to evaluate whether 2021 ESC guidelines vs 2016 and 2019 guidelines improved eligibility of individuals for primary prevention statin therapy before their first STEMI, and for intensive lipid-lowering treatments in secondary prevention and found that:
<ul>
 <li>2019 ESC guidelines helped in improved identification of individuals (mostly women) who are at risk of myocardial infraction (MI), but failed to assign direct statin therapy to 60% of them</li>
 <li>With 2021 ESC guidelines, a significant improvement was noticed in detection of individuals before they have a first MI, with 1/3rd of individuals considered as very-high-risk individuals, and 2/3rd of individuals directly eligible for primary preventive statin therapy 
 <ul>
 <li>The improvement was predominantly noticed in women with previously underestimated cardiovascular (CV) risk</li>
 <li>Despite updating SCORE (systematic coronary risk estimation) to SCORE2, 2021 ESC guidelines have still failed to identify 1/3rd of individuals who are at risk of developing MI</li>
 </ul></li>
 <li>Immediate initiation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitor) after first STEMI could be the next important step to reduce CV death or events and enable an effective and rapid reduction in LDL-C levels</li>
</ul>

<h2>Why This Matter</h2>
<ul>
 <li>The ESC has provided three consecutive guidelines (2016–2021) aiming to prevent CV disease (CVD), with 2019 edition providing updated recommendations on the detection and treatment of individuals at risk in primary and secondary prevention, and 2021 release implemented the use of SCORE2. 
 <ul>
 <li>However, few studies demonstrated limitations in ESC guidelines to detect and recommend primary prevention statins in patients at risk of CVD.</li>
 <li>The real-life effect of the stepwise approach in patients after a first STEMI is unknown.</li>
 </ul></li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>e-PARIS register (Prospective registry of all individuals admitted for a STEMI at the university hospital of Pitié- Salpêtrière) was screened and included patients admitted for a first STEMI between January 2000 and October 2018, with no prior history of CVD and, with available cholesterol samples at the time of admission.</li>
 <li>First objective: To compare 2016, 2019 and 2021 ESC guidelines efficiency to detect and treat men and women, who will develop a first STEMI</li>
 <li>Second objective: Proportion of men and women with hospital follow-ups and eligible for an intensive LLT (lipid lowering therapy) with PCSK9i and ezetimibe based on real-life LDL-C levels</li>
</ul>

<h2>Key Results</h2>
<ul>
 <li>In total 2,757 patients were admitted for first STEMI (648 women [23.5%]). Risk modifiers are more frequent in women than men (especially chronic inflammatory diseases). 
 <ul>
 <li>Median LDL-C at the time of admission for acute MI: Women: 115 mg/dL (IQR [Interquartile range]: 92–151); Men: 121 mg/dl (IQR: 92–151), P = 0.52</li>
 </ul></li>
 <li>Estimation of CV risk in primary prevention:
 <ul>
 <li>Patients considered as very-high-risk (in %): ECS 2019 guidelines (based on clinical factors and SCORE): 17.2%; 2021 guidelines (based on clinical factors and SCORE2): 40.9%</li>
 </ul></li>
 <li>Eligibility for primary prevention intervention in men and women:
 <ul>
 <li>More in 2021 vs 2019 vs 2016 guidelines: 61.8% vs 38.6% vs 24% (P &gt;0.001)</li>
 <li>There was increase in detection of risk (P&nbsp;&lt;0.001) from 2016 to 2021 guidelines, both in men (62.3% vs 35.0% vs 24.9%) and women (60.2% vs 50.7% vs 19.3%).</li>
 </ul></li>
 <li>Guideline-based intensive LLT after a first STEMI according to real-life LDL-C (n = 975):
 <ul>
 <li>After patients were followed up to 33 months after MI, 27% achieved required LDL-C levels of &lt;55 mg/dL and 39% &lt;70 mg/dL.</li>
 <li>Following ECS stepwise approach was used: Among 73% of patients out of LDL-C objective levels, 61.7% patients were eligible to an increase of their statin dosage, 26.2% patients were eligible to add ezetimibe and 12.1% were eligible for PCSK9i therapy</li>
 </ul></li>
 <li>Guideline-based intensive LLT after a first STEMI according to expected LDL-C (n = 2757 patients) [using ESC estimations of LDL-C reduction at discharge]:
 <ul>
 <li>Using 2019/2021 guidelines: Even under full dose and adherence to statins, 38.7% of patients would have LDL-C levels of ≤55 mg/dL; 16.8% of patients would still require ezetimibe; and 44.5% would have LDL-C levels of &gt; 55 mg/dL under statins and ezetimibe and would be eligible for PCSK9i therapy</li>
 <li>Using 2016 guidelines: 14.3% eligible for ezetimibe; 22.5% for PCSK9i for LDL-C levels &lt;70 mg/dL</li>
 </ul></li>
 <li>Control of other cardiovascular risk factors and outcomes:&nbsp;Persistent active smoking was frequent, (men = 35%; women = 14%); HbA1c (glycated hemoglobin) &gt;6.5% in 47% men and 68% women; rate of composite of ACS, stroke or death = 5.1 per 1000 patient-years</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Real life follow-up LDL-C was incomplete.</li>
 <li>Risk modifiers (coronary artery calcium score, carotid plaques, computerized tomography, coronary angiography) were not collected to determine eligibility for statins.</li>
 <li>Patients with Non-ST segment elevated myocardial infraction (NSTEMI) were not analyzed in the study.</li>
 <li>Individual patient response to treatments and compliance were not taken into consideration.</li>
 <li>LDL-C levels were taken within the hour of administration for STEMI.</li>
 <li>Data on statin tolerance in secondary prevention was not collected to decide whether an increase in the dosage was permitted.</li>
</ul>

Dyslipidemia performance of 2016 2019 and 2021 ESC Dyslipidemia guidelines

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