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

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

In this prespecified analysis of the Odyssey Outcomes trial, we investigate the influence of polyvascular disease (PVD) on:
<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>

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

Abbreviations

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

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

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

HRs and p-values reflect stratification by geographic region

<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>

Reference

Odyssey outcomes - PVD results

DYSLIPIDEMIA

CARDIOLOGY

<h2>Alirocumab in patients with polyvascular disease and recent Acute Coronary Syndrome.</h2>
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
<h2>Objective</h2>
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.
<h2>Methods</h2>
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.
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).
<h2>Endpoints</h2>
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.
<h2>Results</h2>
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%).
<h2>Conclusion</h2>
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.

Odyssey Outcomes - PVD Sub-analysis

<h2>Safety and efficacy of alirocumab in patients with Hypercholesterolemia and high cardiovascular risk in a real-life setting</h2>

<h2>Main Takeaway</h2>
<ul>
 <li>
 In high-risk patients with severe hypercholesterolemia&nbsp;receiving maximum tolerated dose (MTD) of statins ± lipid-lowering therapies (LLTs):</li>
 <li>Add-on therapy with&nbsp;alirocumab was shown to be generally well tolerated, with the incidence of treatment-emergent adverse events (TEAEs) being similar to those reported in previous trials.</li>
 <li>Treatment with&nbsp;alirocumab reduced low-density lipoprotein cholesterol (LDL-C) levels by over&nbsp;50% from baseline to Week 12; this was sustained throughout the treatment duration (up to 2 years)</li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>
 Familial hypercholesterolemia (FH) is associated with&nbsp;increased cardiovascular (CV) risk.</li>
 <li>In clinical practice, despite MTD therapy (with or without ezetimibe),&nbsp;many patients with heterozygous FH (HeFH) fail to attain guideline-recommended LDL-C goals&nbsp;without additional LLTs. Statin intolerance remains a concern in some patients, and discontinuation of statin therapy may cause an increase in CV events</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>Odyssey apprise (NCT02476006), a real-life European/Canadian, prospective, single-arm, phase 3b, open-label study, duration ≥12 weeks to ≤30 months, evaluated the safety and efficacy of alirocumab (subcutaneous dosing regimen: 75 or 150 mg every 2 weeks, dose adjustment allowed at investigator’s discretion) 
 <ul>
 <li>Alirocumab was administered on top of background MTD statin (rosuvastatin 20 or 40 mg/day, atorvastatin 40 or 80 mg/day, or simvastatin 80 mg/day) ± other LLTs</li>
 </ul></li>
 <li>Eligibility criteria: Patients aged ≥18 years, with HeFH or with non-familial hypercholesterolemia and established coronary heart disease (CHD) or a CHD risk equivalent, and with hypercholesterolemia not adequately controlled with MTD ± LLT</li>
 <li>Primary endpoint: To assess safety parameters including treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)</li>
 <li>Main secondary (efficacy) endpoint: The percent change in calculated LDL-C from baseline to Week 12</li>
</ul>

<h2>Key Results</h2>
<h3>Safety</h3>
<ul>
 <li>Overall, 994 patients were enrolled and treated, with a mean duration of alirocumab exposure [SD] = 72.4 [42.5] weeks</li>
 <li>Primary endpoint:&nbsp;TEAEs were reported in 712/994 patients
 <ul>
 <li>Four deaths were reported during the on-study period: 2 were during the TEAE period but were not considered as related to alirocumab. Three additional deaths occurred post-study</li>
 <li>45/994 patients permanently discontinued treatment due to a TEAE</li>
 <li>161/994 patients developed TESAEs;&nbsp;9/994 patients were considered to have TESAEs related to alirocumab</li>
 <li>34/994 patients had TEAEs corresponding to AEs of special interest</li>
 </ul></li>
</ul>
<h3>Efficacy</h3>
<ul>
 <li>
 Secondary endpoint: Mean (SD)&nbsp;LDL-C level decreased by 2.6 (1.2) mmol/L&nbsp;from baseline to Week 12 (54.8%; modified intention-to-treat population). This reduction was&nbsp;maintained throughout the study duration</li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>
 The study lacked a comparative control and a treatment bias may exist owing to the open-label design</li>
 <li>Limited applicability of the study findings to other patient populations</li>
 <li>Data on new-onset diabetes and changes in lipoprotein(a) levels were missing</li>
</ul>

Real-life safety and efficacy of Alirocumab - Odyssey apprise study

<h2>Odyssey Outcomes: Addition of PCSK9i to background Statin therapy further reduces MACE.</h2>

<h2>Elderly patients sub-analysis overview</h2>
<h3>Study outcomes</h3>
Primary outcome:&nbsp;composite of death from CHD, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization Key secondary outcome:&nbsp;all-cause death 
 All outcomes were adjudicated by physicians who were unaware of the trial-group assignments
*Pre-specified analysis: Age &lt;65 years (n=13,840), age≥65 years (n=5,084). The Cox regression model with age as a continuous variable, randomized treatment and the interaction was used to estimate the event rate at 3 years and HRs comparing alirocumab versus placebo at specific ages to test the interaction between age and treatment with alirocumab
<h2>Baseline characteristics by age group</h2>
<table align="center" border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td style="width: 51%;">
 Characteristic</td>
 <td style="width: 18%;">
 &lt;65 years (n=13,840)</td>
 <td style="width: 17%;">
 ≥65 years (n=5084)</td>
 <td style="width: 13%;">
 P-value</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Age (years), mean ± SD</td>
 <td style="width: 18%;">
 54.2 ± 6.3</td>
 <td style="width: 18%;">
 70.5 ± 4.7</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Women, n (%)</td>
 <td style="width: 18%;">
 2948 (21.3)</td>
 <td style="width: 17%;">
 1814 (35.7)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Medical history before index ACS, n (%)</td>
 <td style="width: 18%;">
 &nbsp;</td>
 <td style="width: 17%;">
 &nbsp;</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Hypertension</td>
 <td style="width: 18%;">
 8390 (60.6)</td>
 <td style="width: 17%;">
 3859 (75.9)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Diabetes mellitus</td>
 <td style="width: 18%;">
 3787 (27.4)</td>
 <td style="width: 17%;">
 1657 (32.6)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Myocardial infarction</td>
 <td style="width: 18%;">
 2499 (18.1)</td>
 <td style="width: 17%;">
 1134 (22.3)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Percutaneous coronary intervention</td>
 <td style="width: 18%;">
 2212 (16.0)</td>
 <td style="width: 17%;">
 1029 (20.2)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Coronary artery bypass graft</td>
 <td style="width: 18%;">
 582 (4.2)</td>
 <td style="width: 17%;">
 465 (9.1)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Stroke</td>
 <td style="width: 18%;">
 337 (2.4)</td>
 <td style="width: 17%;">
 274 (5.4)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Peripheral artery disease</td>
 <td style="width: 18%;">
 428 (3.1)</td>
 <td style="width: 17%;">
 331 (6.5)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Congestive heart failure</td>
 <td style="width: 18%;">
 1800 (13.0)</td>
 <td style="width: 17%;">
 1014 (19.9)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Index, ACS, n (%)</td>
 <td style="width: 18%;">
 n=13,818</td>
 <td style="width: 17%;">
 n=5075</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 STEMI</td>
 <td style="width: 18%;">
 5039 (36.4)</td>
 <td style="width: 17%;">
 1497 (29.4)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Non-STEMI</td>
 <td style="width: 18%;">
 6422 (46.4)</td>
 <td style="width: 17%;">
 2753 (54.2)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Unstable angina</td>
 <td style="width: 18%;">
 2357 (17.0)</td>
 <td style="width: 17%;">
 825 (16.2)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 PCI or CABG for index ACS, n (%)</td>
 <td style="width: 18%;">
 10,201 (73.7)</td>
 <td style="width: 18%;">
 3475 (68.4)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 </tbody>
</table>
SD, Standard deviation
<table align="center" border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td style="width: 51%;">
 Characteristic</td>
 <td style="width: 18%;">
 &lt;65 years (n=13,840)</td>
 <td style="width: 18%;">
 ≥65 years (n=5084)</td>
 <td style="width: 13%;">
 P-value</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 The from index ACS to randomization 
 (months), mean ± SD</td>
 <td style="width: 18%;">
 3.6 ± 2.8</td>
 <td style="width: 18%;">
 3.8 ± 2.8</td>
 <td style="width: 13%;">
 0.0003</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Body mass index (kg/m2), mean ± SD</td>
 <td style="width: 18%;">
 28.8 ± 4.9</td>
 <td style="width: 18%;">
 27.8 ± 4.6</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Renal function</td>
 <td style="width: 18%;">
 &nbsp;</td>
 <td style="width: 18%;">
 &nbsp;</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 eGFR (mL/min), mean ± SD</td>
 <td style="width: 18%;">
 83.1 ± 18.5</td>
 <td style="width: 18%;">
 70.2 ± 18.2</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 eGFR &lt;60 mL/min, n (%)</td>
 <td style="width: 18%;">
 1,163 (8.4)</td>
 <td style="width: 18%;">
 1,377 (27.1)</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Lipid-lowering drugs at randomization, n (%)</td>
 <td style="width: 18%;">
 &nbsp;</td>
 <td style="width: 18%;">
 &nbsp;</td>
 <td style="width: 13%;">
 &lt;0.0001</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 High-intensity 
 atorvastatin/rosuvastatin</td>
 <td style="width: 18%;">
 12,565 (90.8)</td>
 <td style="width: 18%;">
 4,246 (83.5)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Low- or moderate-intensity atorvastatin/rosuvastatin</td>
 <td style="width: 18%;">
 1,027 (7.4)</td>
 <td style="width: 18%;">
 580 (11.4)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 No statin</td>
 <td style="width: 18%;">
 222 (1.6)</td>
 <td style="width: 18%;">
 238 (4.7)</td>
 <td style="width: 13%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 51%;">
 Ezetibime</td>
 <td style="width: 18%;">
 408 (2.9)</td>
 <td style="width: 18%;">
 142 (2.8)</td>
 <td style="width: 13%;">
 0.57</td>
 </tr>
 </tbody>
</table>

Abbreviation

<h3>Treatment effect by age group: Primary composite outcome</h3>
Relative Risk Reduction Hazard Ratio (Alirocumab vs Placebo) 
 ≥65 years: 0.78, 95% CI 0.68-0.91 
 &lt;65 years: 0.89, 95% CI 0.80-1.00 
 Interaction p-value: 0.19 Absolute Risk Reduction At 3 years (Placebo - Alirocumab) 
 ≥65 years: 3.88%, 95% Cl 1.74-6.02 
 &lt;65 years: 0.91%, 95% Cl -0.13 to 1.95 
 Interaction p-value: 0.015

<h3>Treatment effect by age group: All cause death</h3>
Relative Risk Reduction Hazard Ratio (Alirocumab vs Placebo) 
 ≥65 years: 0.77, 95% CI 0.62-0.95 
 &lt;65 years: 0.94, 95% CI 0.77-1.15 
 Interaction p-value: 0.46 Absolute Risk Reduction At 3 years (Placebo - Alirocumab) 
 ≥65 years: 2.08%, 95% Cl 0.48-3.67 
 &lt;65 years: 0.11%, 95% Cl -0.50 to 1.72 
 Interaction p-value: 0.024

<h2>Safety: Adverse events by age group</h2>
<table align="center" border="1" cellpadding="10" cellspacing="1">
 <tbody>
 <tr>
 <td style="width: 50px;">
 Adverse Event</td>
 <td colspan="2" rowspan="1" style="width: 28px;">
 Randomized Treatment</td>
 <td style="width: 20%;">
 Relative Risk (95%CI) Alirocumab vs Placebo</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &nbsp;</td>
 <td style="width: 14px;">
 Alirocumab, N (%)</td>
 <td style="width: 14%;">
 Placebo, N (%)</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Any adverse event</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 1,974 (79.0)</td>
 <td style="width: 14%;">
 2,042 (79.3)</td>
 <td style="width: 20%;">
 1.00 (0.97 -1.02)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 5,191 (74.7)</td>
 <td style="width: 14%;">
 5,240 (76.3)</td>
 <td style="width: 20%;">
 0.98 (0.96 -1.00)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Serious adverse event</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 703 (28.1)</td>
 <td style="width: 14%;">
 781 (30.3)</td>
 <td style="width: 20%;">
 0.93 (0.85 -1.01)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 1,499 (21.6)</td>
 <td style="width: 14%;">
 1,569 (22.8)</td>
 <td style="width: 20%;">
 0.94 (0.89 -1.00)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Adverse event leading to discontinuation of treatment</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 121 (4.8)</td>
 <td style="width: 14%;">
 128 (5.0)</td>
 <td style="width: 20%;">
 0.97 (0.76 -1.24)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 222 (3.2)</td>
 <td style="width: 14%;">
 196 (2.9)</td>
 <td style="width: 20%;">
 1.12 (0.93 -1.35)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Neurocognitive disorder</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 52 (2.1)</td>
 <td style="width: 14%;">
 65 (2.5)</td>
 <td style="width: 20%;">
 0.82 (0.57 -1.18)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 91 (1.3)</td>
 <td style="width: 14%;">
 102 (1.5)</td>
 <td style="width: 20%;">
 0.88 (0.67 -1.17)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 New-onset diabetes in patients w/o diabetes at baseline</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 156 (9.2)</td>
 <td style="width: 14%;">
 167 (9.7)</td>
 <td style="width: 20%;">
 0.95 (0.77 -1.17)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 492 (9.7)</td>
 <td style="width: 14%;">
 509 (10.2)</td>
 <td style="width: 20%;">
 0.95 (0.84 -1.07)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Hemorrhagic stroke - adjudicated</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 1 (0.0)</td>
 <td style="width: 14%;">
 6 (0.2)</td>
 <td style="width: 20%;">
 0.17 (0.02 -1.42)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 8 (0.1)</td>
 <td style="width: 14%;">
 10 (0.1)</td>
 <td style="width: 20%;">
 0.79 (0.31 -2.00)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Alanine aminotransferase&gt; 3 x upper limit of normal</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 64 (2.6)</td>
 <td style="width: 14%;">
 70 (2.8)</td>
 <td style="width: 20%;">
 0.94 (0.67 -1.31)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 148 (2.1)</td>
 <td style="width: 14%;">
 158 (2.3)</td>
 <td style="width: 20%;">
 0.92 (0.74 -1.15)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 Aspartate</td>
 <td style="width: 14px;">
 &nbsp;</td>
 <td style="width: 14%;">
 &nbsp;</td>
 <td style="width: 20%;">
 &nbsp;</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 ≥65 years</td>
 <td style="width: 14px;">
 52 (2.1)</td>
 <td style="width: 14%;">
 48 (1.9)</td>
 <td style="width: 20%;">
 1.11 (0.75 -1.64)</td>
 </tr>
 <tr>
 <td style="width: 50px;">
 &lt;65 years</td>
 <td style="width: 14px;">
 108 (1.6)</td>
 <td style="width: 14%;">
 118 (1.7)</td>
 <td style="width: 20%;">
 0.90 (0.70 -1.17)</td>
 </tr>
 </tbody>
</table>
<h2>Elderly Patients’ sub-analysis conclusions¹</h2>
<ul>
 <li>Alirocumab demonstrated an effective RRR for primary MACE outcome, and was associated with an effective reduction of all-cause death across age categories</li>
 <li>There was a highly significant interaction of treatment effect and age on the absolute reduction of all-cause death, and although adverse events generally were more frequent in older patients, there was no increase occurrence in any of the safety endpoints</li>
</ul>

Odyssey outcomes - elderly patients results

<h2>Alirocumab reduces total nonfatal cardiovascular and fatal events the Odyssey Outcomes&nbsp;trial.</h2>
Michael Szarek, Harvey D White, Gregory G Schwartz, Marco Alings, Deepak L Bhatt, Vera A Bittner, Chern-En Chiang, Rafael Diaz, Jay M Edelberg, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, J Wouter Jukema, Takeshi Kimura, Robert Gabor Kiss, Guillaume Lecorps, Kenneth W Mahaffey, Angèle Moryusef, Robert Pordy, Matthew T Roe, Pierluigi Tricoci, Denis Xavier, Andreas M Zeiher, Ph Gabriel Steg, Odyssey Outcomes Committees and Investigators.
<h2>Objective</h2>
This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in Odyssey Outcomes.
<h2>Methods</h2>
The Odyssey Outcomes (Evaluation of Cardiovascular outcomes after an Acute Coronary Syndrome during treatment with Alirocumab) trial compared Alirocumab with placebo, added to high-intensity or maximumtolerated statin treatment, after Acute Coronary Syndrome (ACS) in 18,924 patients. Patients were aged ≥40 years with an ACS 1–12 months before randomization. Qualifying patients had persistent dyslipidemia [LDL-C ≥ 70 mg/dL (1.81 mmol/L), non high-density lipoprotein cholesterol (non-HDL-C) ≥ 100 mg/dL (2.59 mmol/L), or apolipoprotein B ≥ 80 mg/dL] despite treatment with atorvastatin 40–80 mg daily, rosuvastatin 20–40 mg daily, or the maximumtolerated dose of one of these statins.
Participants were randomly assigned (1:1) to receive alirocumab 75 mg or matching placebo subcutaneously every 2 weeks.
<h2>Endpoints</h2>
The primary efficacy endpoint of the study was time to first occurrence of coronary heart disease death, nonfatal myocardial infarction, fatal and nonfatal ischemic stroke, or unstable angina requiring hospitalization. Nonfatal cardiovascular events recorded in the trial included nonfatal primary endpoints, hemorrhagic stroke, heart failure requiring hospitalization, and ischemia-driven coronary revascularization. Events included in the primary analysis of the present report were all-cause death and total nonfatal cardiovascular events.
<h2>Results</h2>
Patients were followed for survival for a median of 2.8 years (quartile 1, quartile 3: 2.3, 3.4 years), consisting of 27,014 patient-years for the alirocumab group and 26,915 patient-years for the placebo group.
With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.
<h2>Conclusion</h2>
In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more.
comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

Odyssey Outcomes - Total Events Analysis

<h2>What is TTP?</h2>
Thrombotic thrombocytopenic purpura (TTP)— A rare, life-threatening medical emergency
TTP is a rare, life-threatening thrombotic microangiopathy (TMA). There are approximately 3 cases per million people.1,2 
 The name thrombotic thrombocytopenic purpura describes the 3 main characteristics of the disease.

Thrombotic: characterized by the formation of microthrombi (blood clots) within a blood vessel, which clog the vessel and prevent blood circulation.

Thrombocytopenic: a lower-than-normal platelet count due to the consumption of platelets during microthrombi formation, which causes occlusion of microvasculature.

Purpura: spots of variable size on the skin or in the mucous membranes, due to small hemorrhages; they can be dark red and as small as a pinhead (petechiae) or purplish and 2 to 3 cm in diameter (ecchymosis).

Acquired TTP3,4
<ul>
 <li>aTTP, also known as immune-mediated thrombotic thrombocytopenic purpura (iTTP)</li>
 <li>The most common form of TTP; approximately 95% of TTP cases are aTTP</li>
 <li>Caused by autoantibody inhibition of ADAMTS13 activity.</li>
</ul>
ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13.

Hereditary TTP4,5
<ul>
 <li>Also known as congenital TTP, inherited TTP, familial TTP, or Upshaw–Schulman syndrome</li>
 <li>Very rare form of TTP; mainly detected in children</li>
 <li>Caused by mutations in the ADAMTS13 gene</li>
</ul>

<h2>Primary aTTP vs secondary aTTP2,6,7</h2>

Primary aTTP
<ul>
 <li>Primary aTTP refers to acquired autoimmune TTP for which there is no obvious underlying/precipitating cause/disease</li>
 <li>Primary aTTP accounts for the majority of cases of TTP</li>
</ul>

Secondary aTTP
<ul>
 <li>Secondary aTTP refers to acquired autoimmune TTP for which a defined underlying disorder or trigger can be identified, including connective tissue disease (eg, systemic lupus erythematosus), HIV infection, cytomegalovirus infection, and/or a specific precipitating factor (eg, pregnancy or drugs)</li>
 <li>Treatment of the underlying disorder and/or removal of the underlying precipitant may be required, as well as standard TTP therapy</li>
</ul>

<table border="1" cellpadding="1" cellspacing="1" style="height:100px;width:620px;">
 <tbody>
 <tr>
 <td style="background-color: rgb(241, 135, 0);">
 TTP causes systemic microthrombi and consequent thrombocytopenia, hemolytic anemia, and organ ischemia. These symptoms—coupled with TTP’s rarity—can cause confusion with other TMAs, making TTP a challenge to diagnose.8-10</td>
 </tr>
 </tbody>
</table>

<h2>Signs and symptoms of aTTP include1,7-10</h2>

Petechiae, purpura, bruising (skin)

Headache, confusion, seizures, coma (neurological)

EKG abnormalities (cardiac)

Abdominal pain, diarrhea (gastrointestinal)

Proteinuria/hematuria (kidney)

Suspect aTTP?
<h2 style="text-align: center;">The incidence of TTP is 2 to 6 per million individuals4</h2>

Rare diseases defined as

cases per million&nbsp;11

Ultra-rare diseases defined as

cases per million&nbsp;12

<h2 style="text-align: center;">aTTP primarily affects young, healthy adults13,14</h2>

years of age on average

of people affected are women

higher aTTP incidence in the Black population

<h2 style="text-align: center;">If left untreated, TTP is rapidly fatal8,15-17</h2>

acute mortality rate16,17

of TTP deaths occur within 24 hours of presentation8

<h3 style="text-align: center;">Even with plasma exchange therapy (PEX), mortality risk persists15,16,18</h3>

Up to

acute mortality associated with episodes of aTTP&nbsp;16,18

median time from diagnosis to death 16,18 in acute phase of TTP in patients treated with PEX15,18

References

<h2>The burden of thrombotic thrombocytopenic purpura (TTP)</h2>
Short- and long-term implications threaten patients with aTTP
<h3>Short-term implications</h3>

Mortality
<ul>
 <li>Untreated, aTTP has an acute mortality rate of up to&nbsp;90%1-3</li>
 <li>Approximately 55% to 80% of deaths among patients with aTTP occur within&nbsp;2 weeks of diagnosis4-6</li>
 <li>Significantly higher rates of in-hospital mortality have also been reported in patients with&nbsp;TTP and CV complications(19.7% vs 4.1%)7</li>
</ul>

Health-related quality of life
<ul>
 <li>Rates of depression (10% to 73%) are considerably higher&nbsp;in patients following an episode of TTP, compared with both healthy individuals and reference populations8-12</li>
</ul>

Morbidity
<ul>
 <li>Most common complications&nbsp;in patients hospitalized with TTP&nbsp;are CV complications&nbsp;(25%), such as stroke (10%), heart failure (8%), and acute coronary syndrome (6%)7</li>
</ul>

Economic burden
<ul>
 <li>Short-term treatment of acute thromboembolism such as stroke, acute MI, or TIA&nbsp;requires multiple healthcare resources, including hospitalization with diagnostic tests (eg, CT scans), administration of thrombolytic and/or other drugs, admittance to intensive care/critical care unit, and/or ongoing specialist nursing care (eg, physiotherapy, speech therapy)13-15</li>
</ul>

An increased time at risk of microvascular thrombosis can lead to irreversible organ damage to the heart, brain, and kidneys16
<h3>Long-term implications</h3>

Mortality
<ul>
 <li>23-fold increase in mortality&nbsp;was observed in patients who did not reach a platelet recovery rate of 5 × 109/L per day by day 3 of PEX17</li>
 <li>Inability to normalize platelet count over 7 days of PEX was associated with a&nbsp;significantly increased risk of death18</li>
</ul>

Health-related quality of life
<ul>
 <li>Long-term outcomes are driven by the consequences of platelet aggregation, leading to&nbsp;systemic microvascular thrombosis7,19</li>
</ul>

Morbidity
<ul>
 <li>Recovery following an acute episode of aTTP is not a resolution of symptoms but the beginning of a long-term morbidity burden:&nbsp;hypertension, stroke, and depression requiring pharmacological treatment were significantly greater for TTP survivors&nbsp;versus the age- and sex-matched US population8,9,20</li>
</ul>

Economic burden
<ul>
 <li>Other long-term consequences that have been reported include&nbsp;neurocognitive impairment, depression, hypertension, headaches, and SLE;&nbsp;all require healthcare resources on an ongoing basis11,20</li>
</ul>

<table border="1" cellpadding="1" cellspacing="1" style="width:500px;">
 <tbody>
 <tr>
 <td style="width: 100%; background-color: rgb(241, 135, 0); text-align: center;">Long-term morbidity leads to suboptimal health-related quality of life, in both mental (anxiety, depression) and physical functioning, and potentially reduces life expectancy8-20</td>
 </tr>
 </tbody>
</table>

<h2>The pathophysiology of thrombotic thrombocytopenic purpura (TTP)</h2>
<h3>TTP is characterized by potentially fatal systemic microthrombi1,2</h3>
TTP is caused by severely decreased activity of the ADAMTS13&nbsp;enzyme. ADAMTS13 is the protease that cleaves von Willebrand factor (vWF). In patients with acquired TTP (aTTP), this deficiency is immune mediated.1
Decreased ADAMTS13 activity leads to an accumulation of ultra-large von Willebrand factor (ULvWF) multimers, which spontaneously bind to platelets and induce aggregation. This results in dangerous microthrombi that drive severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia.2
ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13.
<h4>TTP pathophysiology</h4>
An in-depth exploration of the causes of TTP and the severe consequences of the disease.

TTP is a life-threatening thrombotic microangiopathy (TMA) that requires quick diagnosis and urgent treatment.&nbsp;1,2

ACQUIRED-THROMBOTIC-THROMBOCYTOPENIA-PURPURA-ATTP

RARE-BLOOD-DISORDERS

Understanding TTP

<h2>What is the pathophysiology of aTTP?</h2>
<h3>3 Key mechanisms drive the pathophysiology of aTTP2</h3>

<h4 style="text-align: center;">Auto antibody formation</h4>
Autoantibodies to ADAMTS13 inhibit its activity or enhance clearance of the enzyme.

<h4 style="text-align: center;">ADAMTS13 deficiency causes&nbsp;uncleaved ULvWF</h4>
ADAMTS13 (the enzyme responsible for cleaving vWF in the blood-clotting process) is deficient, leaving platelet-hyperadhesive ULvWF strands intact to circulate without being cleaved.

<h4 style="text-align: center;">Microthrombi formation</h4>
ULvWF accumulates and spontaneously binds to platelets, forming microthrombi.

<h3>Thrombotic Thrombocytopenic Purpura2,3</h3>

Adapted from Joly B et al. Blood 2017 and Saad J &amp; Schoenberger L 2018.

<h2>Formation of microthrombi causes2</h2>

<h4 style="text-align: center;">Severe thrombocytopenia</h4>
(often platelets &lt;30 × 109/L)

<h4 style="text-align: center;">Microangiopathic hemolytic anemia 
 (MAHA)</h4>
characterized by the presence of schistocytes in blood smear

<h4 style="text-align: center;">Organ ischemia</h4>
(lesions can occur in any organ, but they most frequently affect the heart, brain, gastrointestinal tract, and kidney)

<table border="1" cellpadding="1" cellspacing="1" style="width:100%;">
 <tbody>
 <tr>
 <td style="text-align: center; background-color: rgb(241, 135, 0); border-color: rgb(241, 135, 0);">
 <h4>Platelet aggregation leads to microthrombi formation, which can have fatal consequences.1,2</h4></td>
 </tr>
 </tbody>
</table>

<h2>Signs and symptoms of aTTP</h2>
The symptoms of aTTP are driven by microthrombi, which are unpredictable and potentially fatal1,2
Microthrombi can have serious acute and chronic consequences in TTP—putting patients at risk for devastating effects and death without urgent treatment.

<h3 style="text-align: center;">Microthrombi can occur in any organ with microvessels, but the most commonly affected are3</h3>

Tissue and organ damage resulting from ischemia leads to increased levels of lactate dehydrogenase (LDH), troponins (heart), and creatinine (kidney).¹,⁴

<h2>Signs and symptoms of acquired thrombotic thrombocytopenic purpura (aTTP) include1,4,5</h2>

&nbsp;of TTP episodes result in ischemia due to platelet aggregation in the microcirculation of the brain.3

<h2>The consequences of microthrombi can be severe, with TTP potentially resulting in acute thromboembolic events such as1,2,4</h2>

<h4>&nbsp;</h4>
<h4>Arterial thrombosis</h4>

<h2>Consequences can also be long term</h2>

TTP is a life-threatening thrombotic microangiopathy (TMA) that requires quick diagnosis and urgent treatment. 1,2

<h2>Odyssey Outcomes: Addition of PCSK9i to background Statin therapy further reduces MACE</h2>

<h2>Mortality study results</h2>
<h3>Effect of Alirocumab on All-Cause, CV or Non-CV death</h3>

*Stratified by geographic region. †Nominal p-value, as all-cause death followed CHD death and cardiovascular death in tile prespecified hierarchy of main secondary endpoints, the p-value for all-cause death was considered nominal
<h2>All-cause death: All patients vs patients eligible for ≥3 years of follow-up</h2>

*Because all-cause death followed CHD death and CV death in the pre specified hierarchy or main secondary endpoints, the p-value for all-cause death was considered nominal. Alirocumab is associated with lower all-cause death as compared to placebo. Patients were eligible for ≥3 years or follow-up if randomized ≥3 years before the common study end date.
**First year HR 1.01 (95% Cl 0.77, 1.32); for patients eligible for &lt;3 years of follow-up HR 0.96 (95% Cl 0.76, 1.21).
<h2>Post-hoc analysis: All-cause death by baseline LDL-C subgroups</h2>

Relative risk reduction: Pinteraction=0.12
Absolute risk reduction: Pinteraction=0.005
*Based on cumulative incidence, alirocumab is associated with lower all-cause death as compared to placebo
<h2>Mortality study conclusions</h2>
<ul>
 <li>The risk of non-CV death is usually assumed to be independent of risk of CV events, and there is unmodifiable risk by LDL-C lowering</li>
 <li>In the post-hoc, joint semiparametric modelling approach, alirocumab treatment was associated with a favorable effect on risk of nonfatal CV events and was a predictor of non-CV death. The association parameter indicates that these risks are linked</li>
</ul>

Odyssey outcomes - mortality

<h2>Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes A prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial</h2>
Kausik K Ray, Helen M Colhoun, Michael Szarek, Marie Baccara-Dinet, Deepak L Bhatt, Vera A Bittner, Andrzej J Budaj, Rafael Diaz, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, J Wouter Jukema, Virginie Loizeau, Renato D Lopes, Angèle Moryusef, Jan Murin, Robert Pordy, Arsen D Ristic, Matthew T Roe, José Tuñón, Harvey D White, Andreas M Zeiher, Gregory G Schwartz, Philippe Gabriel Steg, ODYSSEY OUTCOMES Committees and Investigators

<h2>Objective</h2>
The efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. This study aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycemic status, while also assessing its effects on glycemic measures including risk of new-onset diabetes.

<h2>Endpoints</h2>
The primary endpoint was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. Prespecified secondary outcomes reported here are measures of glycometabolic safety, including the effects of alirocumab on HbA1c and fasting serum glucose concentration, analyzed in the intention-totreat population. New-onset diabetes was analyzed in the safety population.

<h2>Methods</h2>
Multicenter randomized, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1−12 months before randomization and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomization was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)—defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission
Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voiceresponse or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65–1·30 mmol/L. In this prespecified analysis, the effect of alirocumab on cardiovascular events by glycemic status at baseline (diabetes, prediabetes, or normoglycemia)—defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose—and risk of new-onset diabetes among those without diabetes at baseline was investigated.

<h2>Results</h2>
At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycemia.
In the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78–2.46, p&lt;0.0001) and for diabetes versus prediabetes 1.90 (1.65–2.17, p&lt;0.0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2.3%, 95% CI 0.4 to 4.2) than in those with prediabetes (1.2%, 0.0 to 2.4) or normoglycaemia (1.2%, –0.3 to 2.7; absolute risk reduction pinteraction=0.0019). Among patients without diabetes at baseline, 676 (10.1%) developed diabetes in the placebo group, compared with 648 (9.6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1.00, 95% CI 0.89–1.11). HRs were 0.97 (95% CI 0.87–1.09) for patients with prediabetes and 1.30 (95% CI 0.93–1.81) for those with normoglycaemia (pinteraction=0.11).

<h2>Conclusion</h2>
After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65–1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.

Odyssey outcomes - DM sub-analysis

<h2>Effect of Alirocumab on mortality after Acute Coronary Syndrome. An analysis of the Odyssey Outcomes randomized clinical trial.</h2>
Philippe Gabriel Steg, Michael Szarek, Deepak L. Bhatt, Vera A. Bittner, Marie-France Brégeault, Anthony J. Dalby, Rafael Diaz, Jay M. Edelberg, Shaun G. Goodman, Corinne Hanotin, Robert A. Harrington, J. Wouter Jukema, Guillaume Lecorps, Kenneth W. Mahaffey, Angèle Moryusef, Petr Ostadal, Alexander Parkhomenko, Robert Pordy, Matthew T. Roe, Pierluigi Tricoci, Robert Vogel, Harvey D. White, Andreas M. Zeiher, Gregory G. Schwartz, For the Odyssey Outcomes Committees and Investigators
<h2>Objective</h2>
To better understand the effects of alirocumab on death, this report describes all-cause, cardiovascular, and non-cardiovascular death in participants eligible for ≥3 years of follow-up, the interaction of treatment and baseline LDL-C on death, and the association between nonfatal cardiovascular events and non-cardiovascular death.
<h2>Methods</h2>
Odyssey Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Patients were aged ≥40 years with an ACS 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.
Participants were randomly assigned (1:1) to receive alirocumab 75mg or matching placebo subcutaneously every 2 weeks.
<h2>Endpoints</h2>
The primary end point was the composite of death caused by CHD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. To control for multiplicity, secondary end points were analyzed in the following prespecified hierarchical sequence to preserve type I error: any CHD event; major CHD event; any cardiovascular event; the composite of all-cause death, nonfatal myocardial infarction, or ischemic stroke; CHD death; cardiovascular death; and all-cause death.
<h2>Results</h2>
Median follow-up was 2.8 (interquartile range, 2.3–3.4) years. Premature treatment discontinuation for reasons other than death or blind switch to placebo because of low LDL-C levels occurred in 1343 (14.2%) patients receiving alirocumab and 1496 (15.8%) patients receiving placebo.
Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and non-cardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and non-cardiovascular deaths (P&lt;0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P&lt;0.001) and thereby may have attenuated the number of cardiovascular and non-cardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; P interaction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).
<h2>Conclusion</h2>
Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.

Odyssey outcomes - CVOT mortality sub-analysis

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