<p>Ulf Landmesser<sup>1</sup>, Jennifer McGinniss<sup>2</sup>, Ph. Gabriel Steg<sup>3,4</sup>, Deepak L. Bhatt<sup>5</sup>, Vera A. Bittner<sup>6</sup>, Rafael Diaz<sup>7</sup>, Mirza Dilic<sup>8</sup>, Shaun G. Goodman<sup>9,10</sup>,&nbsp;J. Wouter Jukema<sup>11,12</sup>, Megan Loy<sup>13</sup>, Ivan Pećin<sup>14</sup>, Robert Pordy<sup>15</sup>, Steen H. Poulsen<sup>16</sup>, Michael Szarek<sup>17,18</sup>, Harvey D. White<sup>19</sup>, Gregory G. Schwartz<sup>20</sup>, for the ODYSSEY OUTCOMES Investigators.</p>
<h2>Background and Objectives</h2>
<ul>
 <li>The 2019 ESC/EAS dyslipidemia guidelines lowered LDL-C treatment goals: 
  <ul>
   <li>In patients considered at very high risk (including those with ACS), LDL-C goal of &lt;1.4 mmol/L is recommended together with &gt;50% LDL-C reduction and a lower goal of &lt;1.0 mmol/L may be considered for those with recurrent CV events within 2 years</li>
  </ul></li>
</ul>
<ul>
 <li>This analysis, using the data of ODYSSEY OUTCOMES trial: 
  <ul>
   <li>Examined how many patients not at goal with high-intensity or MTD statin treatment achieved new LDL-C treatment goals with alirocumab, according to baseline LDL-C values</li>
   <li>Projected how many would have achieved the new treatment goals with the use of ezetimibe when added to MTD statin therapy</li>
  </ul></li>
</ul>
<h2>Methods</h2>
<ul>
 <li>This sub analysis of the ODYSSEY OUTCOMES trial (multicentre, double-blind, randomized placebo-controlled trial in 18,924 patients of ≥40 years of age, hospitalized with an ACS 1–12 months before randomization) comprised of 17,589 patients with LDL-C ≥1.4 mmol/L at baseline who did not receive ezetimibe treatment</li>
</ul>
<h2>Key Findings</h2>
<ul>
 <li>94.6% of patients receiving alirocumab achieved LDL-C goal &lt;1.4 mmol/L at ≥1 post-baseline measurement vs. 17.3% patients receiving placebo</li>
 <li>85.2% of patients with recurrent CV events vs 3.5% receiving placebo, can achieve the lower goal (&lt;1.0 mmol/L)</li>
 <li>In contrast, addition of ezetimibe to optimized statin therapy was projected to achieve LDL-C &lt;1.4 mmol/L in only 10.6% of patients at baseline</li>
 <li>Although the statin/ezetimibe combination is more cost effective than the statin/PCSK9i combination, a substantial number of patients will not achieve the LDL-C goal with this combination</li>
</ul>
<h2>Conclusion</h2>
<p>In post ACS patients with residual dyslipidemia despite intensive or MTD statin, adding alirocumab treatment which has been shown to further reduce the risk of MACE and is associated with a reduction in all-cause mortality after ACS, enabled majority of the patients to reach the 2019 ESC guideline targets for LDL-C &lt;1.4 mmol/L (&lt;55 mg/dL) and &lt;1.0 mmol/L (&lt;40 mg/dL) compared to placebo or ezetimibe</p>

Abbreviations

References

Achievement of ESC/EAS LDL-C Treatment Goals After an ACS with Statin and Alirocumab

DYSLIPIDEMIA

CARDIOLOGY

<h2>Proprotein convertase subtilisin/kexin type 9 inhibitors for heterozygous familial hypercholesterolemia: A clinical practice experience from the Safeheart registry</h2>

<h2>Key Takeaway</h2>
<p>In clinical practice, PCSK9i (alirocumab or evolocumab) on top of maximum LLT significantly reduced LDL-C levels (by 58%) and improved LDL-C target achievement in patients with heterozygous FH (both in men and women).</p>
<p><strong>LDL-C goals*:</strong></p>
<ul>
 <li>&nbsp;2016 ESC/EAS goals†: Patients with ASCVD = 67%; patients without ASCVD = 80%</li>
 <li>&nbsp;2019 ESC/EAS LDL-C goals‡: VHR patients = 46%; HR patients = 50%</li>
</ul>
<p><strong>Independent predictors for LDL-C goals:</strong>&nbsp;Male gender; smoking; and use of statins + ezetimibe</p>

<h2>Why This Matters</h2>
<ul>
 <li><sup>§</sup>&nbsp;Use of PCSK9i in clinical practice is less frequent (partly due to cost and insurance issues).</li>
 <li>Safeheart&nbsp;registry study assessed the use and efficacy of PCSK9i as well as LDL-C goals attainment in clinical practice setting of FH patients.</li>
</ul>

<h2>Study Design</h2>
<p><strong>Safeheart: Open, Multicenter, Nationwide, Long-term Prospective Study</strong>&nbsp;(N = 433 [Alirocumab = 211; Evolocumab = 222])</p>
<p><strong>Key Inclusion Criteria</strong></p>
<p>Patients with molecular diagnosis of FH (aged ≥20 years) on stable LLT, who received PCSK9i (alirocumab 75/150 mg every 2 or 4 weeks, or evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks) from 2016 to January 2020<sup>¶</sup></p>
<p><strong>Key Exclusion Criteria</strong></p>
<p>Patients who participated in RCTs with PCSK9i before 2016</p>
<p><strong>LDL-C Goals:</strong>&nbsp;Defined and analyzed based on 2016 and 2019 ESC/EAS guidelines</p>

<h2>Key Results</h2>
<p>Overall,&nbsp;<strong>433</strong>&nbsp;patients were included in the analysis</p>
<p>Mean age =&nbsp;<strong>55</strong>&nbsp;years; male =&nbsp;<strong>53%;</strong>&nbsp;history of ASCVD =&nbsp;<strong>39%;</strong>&nbsp;median follow-up =&nbsp;<strong>2.5</strong>&nbsp;years</p>

<h2>LDL-C Levels:</h2>
<ul>
 <li><strong>Before PCSK9i:</strong>&nbsp;Median LDL-C =&nbsp;<strong>145</strong>&nbsp;mg/dL (IQR:&nbsp;<strong>125–173</strong>)</li>
 <li><strong>After addition of PCSK9i:</strong>&nbsp;LDL-C levels reduced by&nbsp;<strong>58%</strong>&nbsp;(IQR:&nbsp;<strong>41–70</strong>&nbsp;<strong>[P &lt;0.001]</strong>) in men and women without differences between both PCSK9i&nbsp;<br>
   Median LDL-C =&nbsp;<strong>62</strong>&nbsp;mg/dL (IQR:&nbsp;<strong>44–87</strong>)</li>
</ul>

<h2>LDL-C Goals*</h2>
<ul>
 <li>2016 ESC/EAS goals†: Patients with ASCVD =&nbsp;<strong>67%</strong>; patients without ASCVD =&nbsp;<strong>80%</strong></li>
 <li>2019 ESC/EAS LDL-C goals‡: VHR patients =&nbsp;<strong>46%</strong>; HR patients =&nbsp;<strong>50%</strong></li>
 <li>Higher LDL-C levels before PCSK9i initiation had a significant inverse relationship with goals attainment</li>
</ul>

<h2>Independent Predictors (2019 ESC/EAS LDL-C GOALS)</h2>
<ul>
 <li>Male gender (P = 0.023); smoking (P = 0.041); and use of statins + ezetimibe (P = 0.008)</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Study lacked blinding randomization</li>
 <li>Follow-up analysis was not centralize</li>
 <li>In the follow-up analysis, Lp(a) measurement was not available</li>
</ul>
<p data-font="legal">* Without differences between alirocumab or evolocumab.<br><sup>†</sup>&nbsp;LDL-C target below 70 mg/dL and 100 mg/dL, respectively according to 2016 ESC/EAS guidelines.<br><sup>‡</sup>&nbsp;LDL-C goal according to 2019 ESC/EAS guidelines (for VHR patients &lt;55 mg/dL; for HR patients &lt;70 mg/dL).<br><sup>§</sup>&nbsp;International guidelines recommend PCSK9i for patients with FH with substantially higher LDL-C levels despite maximally tolerated statin ± ezetimibe.<br><sup>¶</sup>&nbsp;Kept a stable dose of PCSK9i at least 3 months before the last analysis. PCSK9i eligibility was based on Spanish National Health System reimbursement regulations in FH patients.</p>

Reference

Clinical practice experience in patients with familial hypercholesterolemia (FH) from the Safeheart registry

<h2>Achievement of lipid modification goals relating to statins and ezetimibe use for cardiovascular disease prevention in the United Kingdom</h2>
<p>This review emphasized on various reasons for sub-optimal lipid lowering and provided possible strategies for improving lipid management to reduce cardiovascular disease (CVD) risk in practice considering the United Kingdom (UK) clinical guidance.</p>
<h2>Key Takeaway</h2>
<ul>
 <li>This review highlighted that a significant proportion of UK patients with CVD have sub-optimal reductions in cholesterol/non-high-density lipoprotein cholesterol (HDL-C)/ low-density lipoprotein cholesterol (LDL-C) despite the widespread availability of lipid-lowering therapy and guidance.</li>
 <li>Reasons for sub-optimal lipid lowering are multifactorial, including a lack of compliance with guidelines, patient adherence, statin intolerance, and statin reluctance as well as wider genetic factors.</li>
 <li>Possible strategies that improve current lipid management and attainment of lipid-lowering goals include: 
  <ul>
   <li>Improving the patient–healthcare professional partnership; conducting audits of local prescribing versus guidance; implementing plans for the refinement of current services; considering alternative options that improve adherence (cost-effective single-pill combinations)</li>
  </ul></li>
 <li>Additional options are needed in patients at a high risk of CVD events, in whom lipid-lowering goals are not achieved with statins and ezetimibe alone.</li>
</ul>
<h2>Why This Matters</h2>
<ul>
 <li>Despite accepting LDL-C as a causal cardiovascular risk factor and thus a critical component in CVD risk reduction, lipid lowering is not adequately attained in the UK.</li>
 <li>This review was conducted to understand current UK lipid management guidance in relation to treatment with statins and ezetimibe and the corresponding attainment of recommended lipid-lowering goals, with a focus on publications between January 2017 and February 2020.</li>
</ul>
<h2>Key Highlights</h2>
<p>Identified publications were reviewed against lipid management guidelines in relation to CVD risk from National Institute for Health and Care Excellence (NICE, CG181), Scottish Intercollegiate Guidelines Network (SIGN, 149), and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS).</p>
<p>Lipid management in the UK:</p>
<ul>
 <li>NICE CG181 (updated in 2016) and SIGN 149 (2017) are the main clinical guidelines for lipid management in relation to cardiovascular risk in the UK.</li>
 <li>Current UK guidelines advise that lipid-lowering therapy should be considered for both the primary and secondary prevention of CVD based on CVD risk assessment (10 year) in addition to recommending lifestyle modifications.</li>
 <li>Although a range of lipid-modifying therapies are approved in the UK, statins are the mainstay of initial recommended treatment strategies.</li>
 <li>NICE and SIGN guidance recommend that lipid-lowering therapy should achieve &gt;40% reduction in non-HDL-C at 3 months.</li>
 <li>ESC/EAS guidelines highlight lowering LDL-C and total cholesterol as the primary target of therapy.</li>
 <li>LDL-C measurement remains relevant in routine clinical practice as the guidance for later lines of therapy (post-statin) is predicated on the evaluation of LDL-C levels.</li>
 <li>NICE states that ezetimibe should be considered in combination with statin for primary hypercholesterolemia when total cholesterol or LDL-C is not adequately controlled after initial statin therapy.</li>
 <li>Alternative therapies such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab or alirocumab may be considered for certain patients with hypercholesterolemia or mixed dyslipidemia who have a high or very high risk of CVD, but only if LDL-C levels are persistently above recommended thresholds.</li>
 <li>Recent ESC/EAS guidelines also state that if patients fail to achieve LDL-C goal within 4–6 weeks despite lifestyle modifications and maximally tolerated highintensity statins, add-on therapy with ezetimibe and subsequently a PCSK9 inhibitor should be considered.</li>
</ul>
<p>Sub-optimal achievement of guideline-derived lipid modification goals:</p>
<ul>
 <li>Several large UK studies highlighted that a significant proportion of patients are not being adequately managed according to best practice guidelines despite widespread availability and supporting evidence on the effectiveness of statins and combination therapy with ezetimibe.</li>
 <li>Variations in individual patient genotypes, statin intolerance, patient adherence, and the potency of statin prescribing might be reasons for sub-optimal LDL-C reductions.</li>
 <li>Limited prescribing of combination therapy may also contribute to sub-optimal lipid lowering.</li>
 <li>Other factors likely to contribute to sub-optimal lipid lowering include late intervention in the disease trajectory, a lack of follow-up and treatment adaptation according to risk factors or fulfillment of therapeutic goals, and statin intolerance.</li>
 <li>Misconceptions about statin intolerance and statin-related adverse events may lead to a reluctance to take statins and early discontinuation and/or non-adherence, which may result in inadequate lipid lowering.</li>
</ul>
<p>Possible strategies that improve current lipid management include*:</p>
<ul>
 <li>Measures for improving the patient–healthcare professional partnership; conducting audits of local prescribing versus guidance; implementing plans for the refinement of current services; follow-up and monitoring procedures for different types of therapy; and considering alternative options that improve treatment adherence (cost-effective single pill)</li>
</ul>
<p>Additional information:</p>
<ul>
 <li>Possible strategies that improve adherence with cholesterol goals*</li>
</ul>

Achievement of lipid modification goals with Statins & Ezetimibe

<h2>Safety and Efficacy of Ezetimibe Added on to Rosuvastatin 5 or 10 mg Versus Up-Titration of Rosuvastatin in Patients with Hypercholesterolemia (the ACTE Study)</h2>
<p>Harold E Bays, Michael H Davidson, Rachid Massaad, Doreen Flaim, Robert S Lowe, Andrew M Tershakovec, Charlotte Jones-Burton</p>
<h2>Objective</h2>
<p>The primary objective of the present study was to compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of ezetimibe added to stable rosuvastatin therapy (5 or 10 mg/day) versus doubling the rosuvastatin dose (from 5 to 10 mg/day or 10 to 20 mg/ day, pooled across doses).</p>
<h2>Endpoints</h2>
<p>The primary efficacy endpoint was the percentage of change from baseline in LDL cholesterol evaluated in the overall population (pooled across doses). The evaluation of this endpoint for each stratum separately, and the percentage of subjects reaching the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommended LDL cholesterol targets in the overall population (pooled across doses) constituted the key secondary efficacy endpoints. Other secondary efficacy endpoints included the percentage of subjects reaching the NCEP ATP III recommended LDL cholesterol targets evaluated in each stratum separately; the percentage of subjects achieving an LDL cholesterol level of &lt;70 mg/dl in the overall population and in each stratum separately; and the percentage of change from baseline in other lipids, lipoproteins, and high-sensitivity C-reactive protein evaluated in the overall population and in each stratum separately. Safety and tolerability were assessed by review of all safety parameters, including adverse experiences and laboratory values.</p>
<h2>Methods</h2>
<p>The 6-week, randomized, double-blind, parallel-arm study included patients who were hypercholesterolemic, aged 18 to 79 years with a moderately high risk (subjects with ≥2 risk factors conferring a 10-year risk of CHD of 10% to 20%, as estimated from the Framingham risk scores), high risk without AVD (subjects with CHD risk equivalents such as diabetes mellitus or ≥2 risk factors conferring a 10-year risk of CHD ≥20%, as estimated from the Framingham risk scores), or high risk with AVD (subjects with established CHD or patients with CHD risk equivalents and other AVD [peripheral arterial disease, atherosclerotic aortic disease, or carotid artery disease]).</p>
<p>Once eligible, patients were assigned to receive run-in open-label rosuvastatin 5 or 10 mg/day for 4 weeks (5 weeks for those switching medication or treatment naïve) according to their cardiovascular risk, current use of lipid lowering therapy, and LDL level at screening. Patients were stratified according to their runin treatment (stratum I, rosuvastatin 5 mg; stratum II, rosuvastatin 10 mg). The subjects receiving rosuvastatin 5 mg during the run-in period (stratum I) were randomized to rosuvastatin 5 mg plus ezetimibe 10 mg add-on or rosuvastatin up-titration to 10 mg. Those receiving rosuvastatin 10 mg (stratum II) were randomized to rosuvastatin 10 mg plus ezetimibe 10 mg add-on or rosuvastatin up-titration to 20 mg.</p>
<h2>Results</h2>
<p>440 patients were administered the study drug, with 197 (44.8%) receiving rosuvastatin 5 mg and 243 (55.2%) receiving rosuvastatin 10 mg during the 4- to 5-week open label run-in period. Pooled data demonstrated that ezetimibe added to stable rosuvastatin 5 mg or 10 mg reduced LDL cholesterol by 21%. In contrast, doubling rosuvastatin to 10 mg or 20 mg reduced LDL cholesterol by 5.7% (between-group difference of 15.2%, p &lt;0.001). Individually, ezetimibe plus rosuvastatin 5 mg reduced LDL cholesterol more than did rosuvastatin 10 mg (12.3% difference, p &lt;0.001), and ezetimibe plus rosuvastatin 10 mg reduced LDL cholesterol more than did rosuvastatin 20 mg (17.5% difference, p &lt;0.001). Compared to rosuvastatin up-titration, ezetimibe add-on achieved significantly greater attainment of LDL cholesterol levels of &lt;70 or &lt;100 mg/dl (59.4% vs 30.9%, p &lt;0.001), and &lt;70 mg/dl in all subjects (43.8% vs 17.5%, p &lt;0.001); produced significantly greater reductions in total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B (p &lt;0.001); and resulted in similar effects on other lipid parameters. Adverse experiences were generally comparable among the groups.</p>
<h2>Conclusions</h2>
<p>compared to up-titration doubling of the rosuvastatin dose, ezetimibe 10 mg added to stable rosuvastatin 5 mg or 10 mg produced greater improvements in many lipids’ parameters and achieved greater attainment of recommended LDL cholesterol targets in subjects with elevated LDL cholesterol and at moderately high/high coronary heart disease risk.</p>

The ACTE Study

<h2>Efficacy and Safety of Rosuvastatin 40 mg Alone or in Combination with Ezetimibe in Patients at High Risk of Cardiovascular Disease (Results from the EXPLORER Study)</h2>
<p>Christie M Ballantyne, Robert Weiss, Tiziano Moccetti, Anja Vogt, Bernd Eber, Froukje Sosef, Emma Duffield, EXPLORER Study Investigators</p>
<h2>Objective</h2>
<p>The aim of the "EXPLORER (EXamination of Potential Lipid-modifying effects Of Rosuvastatin in combination with Ezetimibe versus Rosuvastatin alone)" study is to compare the efficacy and safety of the most effective and highest marketed dose of rosuvastatin (40 mg) alone or in combination with ezetimibe 10 mg for 6 weeks in high-risk patients with hypercholesterolemia.</p>
<h2>Endpoints:</h2>
<p>In This 6-week, open-label, randomized, parallel-group study, Patients were required to discontinue lipid-lowering therapy before entering a 6-week dietary lead-in period. Eligible patients then were randomly assigned (1:1) to treatment with rosuvastatin 40 mg monotherapy or rosuvastatin 40 mg/ezetimibe 10 mg combination therapy.</p>
<p>Patients were Men and women aged ≥18 years with hypercholesterolemia and a history of CHD or clinical evidence of atherosclerosis or a CHD risk equivalent (10- year CHD risk score &gt;20%) were eligible for randomization if the mean of their 2 most recent fasting LDL cholesterol levels was ≥160 mg/dl and &lt;250 mg/dl and the 2 measurements were within 15% of each other. Eligible patients were also required to have a fasting triglyceride (TG) concentration of &lt;400 mg/dl.</p>
<h2>Methods</h2>
<p>The primary endpoint was the percentage of patients achieving the Adult Treatment Panel III (ATP III) LDL cholesterol goal (&lt;100 mg/dl) after 6 weeks of treatment. Secondary efficacy endpoints included the percentage of patients achieving the ATP III non–high-density lipoprotein (non-HDL) cholesterol goal (non-HDL cholesterol &lt;130 mg/dl and LDL cholesterol &lt;100 mg/dl when baseline TG ≥200 mg/ dl); 2003 European LDL cholesterol goals (&lt;2.5 or 3.0 mmol/L [100 or 115 mg/dl], depending on risk category); combined 2003 European LDL cholesterol and total cholesterol (TC) goals (LDL cholesterol &lt;2.5 or 3.0 mmol/L [&lt;100 or 115 mg/dl] and TC &lt;4.5 or 5.0 mmol/L [&lt;175 or 190 mg/dl], depending on risk category); and percent change from baseline in LDL cholesterol, HDL cholesterol, TC, TG, non-HDL cholesterol, lipid ratios (LDL/HDL cholesterol, TC/HDL cholesterol, and nonHDL/HDL cholesterol), apolipoprotein A-I, apolipoprotein B, and apolipoprotein B/apolipoprotein A-I ratio, and changes in high sensitivity C-reactive protein (hs-CRP) at week 6.</p>
<h2>Results:</h2>
<p>469 were randomly assigned (230 to rosuvastatin 40-mg monotherapy and 239 to rosuvastatin 40-mg plus ezetimibe 10-mg combination therapy). Significantly more patients receiving rosuvastatin/ezetimibe than rosuvastatin alone achieved their ATP III LDL cholesterol goal (&lt;100 mg/dl, 94.0% vs 79.1%, p &lt;0.001) and the optional LDL cholesterol goal (&lt;70 mg/dl) for very high-risk patients (79.6% vs 35.0%, p &lt;0.001). The combination of rosuvastatin/ezetimibe reduced LDL cholesterol significantly more than rosuvastatin (-69.8% vs -57.1%, p &lt;0.001). Other components of the lipid/lipoprotein profile were also significantly (p &lt;0.001) improved with rosuvastatin/ezetimibe. Significantly (p &lt;0.001) greater decreases in TC, non-HDL cholesterol, and TGs were also observed at week 6 in the combination therapy group compared with the monotherapy group. Significant decreases in apolipoprotein B and apolipoprotein B/apolipoprotein A-I ratio were observed in the combination therapy group compared with the monotherapy group (p &lt;0.001 for both). Apolipoprotein A-I increased by 3.2% and 1.6% in the combination therapy and monotherapy groups, respectively (p = 0.202). median percent decrease in hs-CRP was significantly higher with combination therapy than monotherapy (-46.4% vs -28.6%, p &lt;0.001). Both treatments generally were well tolerated. Rosuvastatin 40 mg was effective at improving the atherogenic lipid profile in this high-risk population. Combination rosuvastatin with ezetimibe 10 mg enabled greater decreases in LDL cholesterol and allowed more patients to achieve LDL cholesterol goals.</p>
<h2>Conclusion:</h2>
<p>Rosuvastatin plus ezetimibe may improve the management of high-risk patients who cannot achieve goal on maximal statin monotherapy.</p>

The Explorer Study

<h2>Odyssey Outcomes: Addition of PCSK9i to Background Statin Therapy Further Reduces MACE.</h2>

<h2>Total events study results</h2>
<h3>Study methods</h3>
<ul>
 <li>Prespecified joint semiparametric model that allows for multiple nonfatal events within a given patient</li>
 <li>Separate hazard functions for nonfatal and fatal events</li>
 <li>Association parameter quantifies the strength of the relationship between risk of nonfatal and fatal events; positive value indicates patients at high risk for nonfatal events also at high risk of death</li>
 <li>All analyses conducted according to intention-to-treat, including all patients and adjudicated events from randomization to the common study end date<br>
   &nbsp;</li>
</ul>

<h3>Alirocumab reduced total events</h3>
<p>5,425 total nonfatal CV events or deaths; 77% greater than first events</p>
<p>Among patients with a first nonfatal CV event:</p>
<ul>
 <li>82%* of alirocumab patients and 85% of placebo patients were on assigned treatment; all but four alirocumab patients and three placebo patients continued treatment after first event</li>
 <li>1,261 (48%) had at least one additional event</li>
</ul>

<h2>Nonfatal CV events were associated with Total Mortality</h2>
<p><strong>Table 4</strong> Joint Semiparametric Models</p>
<table border="1" cellpadding="10" cellspacing="1">
 <tbody>
  <tr>
   <td>HR (95%CI)</td>
   <td>p Value</td>
   <td>&nbsp;</td>
  </tr>
  <tr>
   <td>Death and total nonfatal cardiovascular events (n = 5,425)</td>
   <td>&nbsp;</td>
   <td>&nbsp;</td>
  </tr>
  <tr>
   <td>Alirocumab: placebo HR for nonfatal cardiovascular events (n = 2,186 vs. n = 2,513)</td>
   <td>0.87 (0.82-0.93)</td>
   <td>&lt;0.0001</td>
  </tr>
  <tr>
   <td>Alirocumab: placebo HR for fatal events (n = 334 vs. n = 392)</td>
   <td>0.83 (0.71-0.97)</td>
   <td>0.02</td>
  </tr>
  <tr>
   <td>Association between nonfatal cardiovascular and fatal events 2.04 (95% CI: 1.78-2.29)</td>
   <td>-</td>
   <td>&lt;0.0001</td>
  </tr>
  <tr>
   <td>Death and total nonfatal MI, stroke, or UA events (n = 2,999)</td>
   <td>&nbsp;</td>
   <td>&nbsp;</td>
  </tr>
  <tr>
   <td>Alirocumab: placebo HR for nonfatal myocardial infarction, stroke, or unstable angina (n = 1,034 vs. n = 1,239)</td>
   <td>0.84 (0.77-0.91)</td>
   <td>&lt;0.0001</td>
  </tr>
  <tr>
   <td>Alirocumab: placebo HR for fatal events (n = 334 vs. n = 392)</td>
   <td>0.82 (0.68-0.99)</td>
   <td>0.04</td>
  </tr>
  <tr>
   <td>Association between nonfatal and fatal events 3.29 (95% CI: 2.86-3.72)</td>
   <td>&nbsp;</td>
   <td>0.0001</td>
  </tr>
 </tbody>
</table>
<p>In relation to nonfatal events and death risk association, the post-hoc model association parameter was 1.70 (1.44, 1.96), p&lt;0.0001</p>

<h3>Higher baseline LDL-C associated with greater reduction of total events with Alirocumab</h3>
<ul>
 <li>255 fewer total events with alirocumab among 5,629 patients with LDL-C &gt;100 mg/dl at baseline</li>
 <li>130 fewer total events with alirocumab among 13,295 patients with LDL-C</li>
</ul>

<h2>Total events study conclusion</h2>
<ul>
 <li>In the previously reported primary analysis of the study data, the observed 15% relative risk reduction (RRR) in allcause death with alirocumab was considered nominally significant due to the prespecified testing sequence of secondary endpoints</li>
 <li>The joint models showed an associated reduction in non-fatal CV events and was a predictor of non-fatal CV mortality by alirocumab</li>
 <li>The authors in the manuscript conclude that this complementary modelling strategy therefore supports the observation that alirocumab reduced all-cause death in the trial</li>
 <li>They further discuss that reduction in mortality risk may be viewed as a preferred metric to summarise the observed effect of treatment with alirocumab on mortality</li>
</ul>

Odyssey outcomes - total events results

<h2>Optimal utilization of lipid-lowering therapy (LLT) after acute coronary syndrome (ACS)</h2>
<h3>A Position Paper endorsed by the International Lipid Expert Panel (ILEP)</h3>
<h2>Main takeaway</h2>
<p>Recommendations include&nbsp;<strong>a main treatment pathway (diagnosis and stratification/target-driven LLT/support and follow-up)</strong>, along with special pathways for a few specific clinical practice scenarios.</p>
<h2>Why this matters</h2>
<p>This position paper&nbsp;<strong>complements existing guidelines on the management of lipids in patients after ACS</strong>&nbsp;and proposes&nbsp;<strong>practical approaches to improve access/adherence to LLTs</strong>&nbsp;in these patients.</p>
<h2>Key results</h2>
<ul>
 <li>Main pathway for optimal LLT post ACS includes the following: 
  <ul>
   <li>Diagnosis and stratification</li>
   <li>Target-driven LLT: Three stage target-driven approach to LLT 
    <ul>
     <li>In statin-treated patients with LDL-C &lt;100 mg/dL, statin therapy has to be intensified to maximally tolerated dose. In statin-naïve patients with LDL-C &lt;120 mg/dL, high-dose atorvastatin or rosuvastatin treatment should be commenced (&lt;50% reduction to reach target [target LDL-C: &lt;55 mg/dL]; for both the cases).</li>
     <li>In statin-treated patients with LDL-C 100–300 mg/dL or in statin-naïve patients with LDL-C 120–300 mg/dL, maximally tolerated statin therapy should be combined with ezetimibe (50–80% reduction to reach target [target LDL-C: &lt;55 mg/dL]).</li>
     <li>In any patient with LDL-C &gt;300 mg/dL on admission, triple therapy (maximally tolerated statin therapy + ezetimibe + PCSK9i) might be initiated in hospital (&gt;80% reduction to reach target [target LDL-C: &lt;55 mg/dL]).</li>
     <li>After the 4–6 week follow-up visit, treatment should be intensified (as per need), to reach the target LDL-C level; less frequent follow-up is acceptable after reaching the target LDL-C level.</li>
    </ul></li>
   <li>Support and follow-up 
    <ul>
     <li>To maximize adherence to treatment, follow-up, and escalation of LLT, a standardized discharge letter should be used.</li>
    </ul></li>
  </ul></li>
 <li>Treatment recommendations for patients in need of special pathways (as identified during diagnosis and stratification): 
  <ul>
   <li>Patients considered to be at “extremely-high” CV risk: Initial immediate dual LLT should be considered (maximally tolerated statin + ezetimibe [target LDL-C: &lt;40 mg/dL]). A PCSK9i can be prescribed at follow-up, if the target is not met.</li>
   <li>In patients with complete statin intolerance: Treatment should proceed immediately with non-statin LLT; in case of partial statin intolerance, early initiation of additional LLTs + low dose of statin should be considered to attain the LDL-C target of &lt;55 mg/dL.</li>
   <li>If target LDL-C is not attained despite receiving maximally tolerated statin dose and ezetimibe in pre-hospital period: PCSK9i initiation should be considered during hospitalization.</li>
  </ul></li>
</ul>

Optimal use of LLT after ACS

<h2>Polyvascular Disease Sub-analysis Overview</h2>
<h3>Alirocumab in Patients with Polyvascular Disease and Recent Acute Coronary Syndrome</h3>
<h3>Objective</h3>

<p>In this prespecified analysis of the Odyssey Outcomes trial, we investigate the influence of polyvascular disease (PVD) on:</p>
<ul>
 <li>Risks of MACE and death in patients with recent ACS and dyslipidemia despite intensive statin therapy</li>
 <li>The modification of risk by alirocumab</li>
</ul>

<p>For the heterogeneity of alirocumab treatment effed by polyvascular disease category, Cox models were used for interaction terms for relative risk reduction and Gail-Simon tests for AR</p>

<h2>Primary MACE: One, two or three vascular beds</h2>

<p>RRR interaction p=0.40. *In overall population, there were no differences in the incidence of adverse events or laboratory abnormalities between alirocumab and placebo groups, except for local injection-site reactions</p>

<h2>Death: One, two or three vascular beds</h2>

<p>HRs and p-values reflect stratification by geographic region</p>

<h2>Polyvascular disease sub-analysis conclusions</h2>
<ul>
 <li>Increasing risk of death in patients with affected vascular beds remain a challenge for clinicians</li>
 <li>This study demonstrates that PVD is associated with high risk of death, and yet with alirocumab, the corresponding ARR for incidence of death was 0.4% (P-interaction = 0.002)</li>
 <li>Alirocumab, when added to high-intensity statin therapy, was associated with a reduction in mortality in this group of patients</li>
</ul>

Odyssey outcomes - PVD results

<h2>Alirocumab in patients with polyvascular disease and recent Acute Coronary Syndrome.</h2>
<p>J Wouter Jukema, Michael Szarek, Laurien E Zijlstra, H Asita de Silva, Deepak L Bhatt, Vera A Bittner, Rafael Diaz, Jay M Edelberg, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, Yuri Karpov, Angèle Moryusef, Robert Pordy, Juan C Prieto, Matthew T Roe, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, P Gabriel Steg, Odyssey Outcomes Committees and Investigators</p>
<h2>Objective</h2>
<p>This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.</p>
<h2>Methods</h2>
<p>The trial was a randomized, double-blind, placebo-controlled comparison of alirocumab or placebo in patients with an ACS (myocardial infarction or unstable angina) 1–12months before randomization. Qualifying patients had persistent dyslipidemia [LDL-C≥ 70mg/dL (1.81mmol/L), non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 100mg/dL (2.59mmol/L), or apolipoprotein B≥ 80mg/dL despite treatment with atorvastatin 40–80 mg daily, rosuvastatin 20–40mg daily, or the maximum-tolerated dose of one of these statins.</p>
<p>Participants were randomly assigned (1:1) to receive alirocumab 75mg or matching placebo subcutaneously every 2weeks. In this analysis, 3 subgroups of patients with recent ACS were defined on the basis of the distribution of other evident vascular disease: 1) monovascular disease (CAD without known PAD or CeVD); 2) polyvascular disease in 2 vascular beds (CAD and either PAD or CeVD); and 3) polyvascular disease in 3 vascular beds (CAD with both PAD and CeVD).</p>
<h2>Endpoints</h2>
<p>The primary outcome was a composite of MACE, including death due to coronary heart disease, non-fatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. Death from any cause was a secondary outcome.</p>
<h2>Results</h2>
<p>A total of 18 924 patients underwent randomization; Of these, 9462 were assigned to alirocumab and 9462 to placebo with a median (quartile 1, quartile 3) follow-up of 2.8 years (2.3, 3.4 years). Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: -2.4% to 6.2%), and 13.0% (95% CI: -2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: -0.1% to 1.0%), 1.3% (95% CI: -1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%).</p>
<h2>Conclusion</h2>
<p>Patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients.</p>

Odyssey Outcomes - PVD Sub-analysis

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