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

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

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

<p><strong>Purpura</strong>: 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).</p>

<p><strong>Acquired TTP<sup>3,4</sup></strong></p>
<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 <strong>autoantibody inhibition of ADAMTS13 activity.</strong></li>
</ul>
<p data-font="legal">ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13.</p>

<p>Hereditary TTP<sup>4,5</sup></p>
<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 <strong>mutations in the ADAMTS13 gene</strong></li>
</ul>

<h2>Primary aTTP vs secondary aTTP<sup>2,6,7</sup></h2>

<p><strong>Primary aTTP</strong></p>
<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>

<p><strong>Secondary aTTP</strong></p>
<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);">
    <p style="text-align: center;"><strong><span style="color:#ffffff;">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</span></strong></p></td>
  </tr>
 </tbody>
</table>

<h2>Signs and symptoms of aTTP include<sup>1,7-10</sup></h2>

<p style="text-align: center;">Petechiae, purpura, bruising (skin)</p>

<p style="text-align: center;">Headache, confusion, seizures, coma (neurological)</p>

<p style="text-align: center;">EKG abnormalities (cardiac)</p>

<p style="text-align: center;">Abdominal pain, diarrhea (gastrointestinal)</p>

<p style="text-align: center;">Proteinuria/hematuria (kidney)</p>

<p style="text-align: center;"><strong>Suspect aTTP?</strong></p>
<h2 style="text-align: center;">The incidence of TTP is 2 to 6 per million individuals<sup>4</sup></h2>

<p style="text-align: center;"><strong>Rare diseases defined as</strong></p>

<p style="text-align: center;">cases per million&nbsp;<sup>11</sup></p>

<p style="text-align: center;"><strong>Ultra-rare diseases defined as</strong></p>

<p style="text-align: center;">cases per million&nbsp;<sup>12</sup></p>

<h2 style="text-align: center;">aTTP primarily affects young, healthy adults<sup>13,14</sup></h2>

<p style="text-align: center;"><strong>years of age on average</strong></p>

<p style="text-align: center;"><strong>of people affected are women</strong></p>

<p style="text-align: center;"><strong>higher aTTP incidence in the Black population</strong></p>

<h2 style="text-align: center;">If left untreated, TTP is rapidly fatal<sup>8,15-17</sup></h2>

<p style="text-align: center;"><strong>acute mortality rate<sup>16,17</sup></strong></p>

<p style="text-align: center;"><strong>of TTP deaths occur within 24 hours of presentation<sup>8</sup></strong></p>

<h3 style="text-align: center;">Even with plasma exchange therapy (PEX), mortality risk persists<sup>15,16,18</sup></h3>

<p style="text-align: center;"><strong>acute mortality associated with episodes of aTTP&nbsp;<sup>16,18</sup></strong></p>

<p style="text-align: center;"><strong>median time from diagnosis to death 16,18 in acute phase of TTP in patients treated with PEX<sup>15,18</sup></strong></p>

References

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

<p><strong>Mortality</strong></p>
<ul>
 <li>Untreated, aTTP has an acute mortality rate of up to&nbsp;<strong>90%</strong><sup>1-3</sup></li>
 <li>Approximately 55% to 80% of deaths among patients with aTTP occur within&nbsp;<strong>2 weeks of diagnosis</strong><sup>4-6</sup></li>
 <li>Significantly higher rates of in-hospital mortality have also been reported in patients with&nbsp;<strong>TTP and CV complications</strong>(19.7% vs 4.1%)<sup>7</sup></li>
</ul>

<p><strong>Health-related quality of life</strong></p>
<ul>
 <li><strong>Rates of depression (10% to 73%) are considerably higher</strong>&nbsp;in patients following an episode of TTP, compared with both healthy individuals and reference populations<sup>8-12</sup></li>
</ul>

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

<p><strong>Economic burden</strong></p>
<ul>
 <li>Short-term treatment of acute thromboembolism such as stroke, acute MI, or TIA&nbsp;<strong>requires multiple healthcare resources</strong>, 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)<sup>13-15</sup></li>
</ul>

<p><strong>An increased time at risk of microvascular thrombosis can lead to irreversible organ damage to the heart, brain, and kidneys<sup>16</sup></strong></p>
<h3>Long-term implications</h3>

<p><strong>Mortality</strong></p>
<ul>
 <li><strong>23-fold increase in mortality</strong>&nbsp;was observed in patients who did not reach a platelet recovery rate of 5 × 109/L per day by day 3 of PEX<sup>17</sup></li>
 <li>Inability to normalize platelet count over 7 days of PEX was associated with a&nbsp;<strong>significantly increased risk of death</strong><sup>18</sup></li>
</ul>

<p><strong>Health-related quality of life</strong></p>
<ul>
 <li>Long-term outcomes are driven by the consequences of platelet aggregation, leading to&nbsp;systemic microvascular thrombosis<sup>7,19</sup></li>
</ul>

<p><strong>Morbidity</strong></p>
<ul>
 <li>Recovery following an acute episode of aTTP is not a resolution of symptoms but the beginning of a long-term morbidity burden:<strong>&nbsp;hypertension, stroke, and depression requiring pharmacological treatment were significantly greater for TTP survivors</strong>&nbsp;versus the age- and sex-matched US population<sup>8,9,20</sup></li>
</ul>

<p><strong>Economic burden</strong></p>
<ul>
 <li>Other long-term consequences that have been reported include&nbsp;<strong>neurocognitive impairment, depression, hypertension, headaches, and SLE;</strong>&nbsp;all require healthcare resources on an ongoing basis<sup>11,20</sup></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;"><span style="color:#ffffff;"><strong>Long-term morbidity leads to suboptimal health-related quality of life, in both mental (anxiety, depression) and physical functioning, and potentially reduces life expectancy<sup>8-20</sup></strong></span></td>
  </tr>
 </tbody>
</table>

Abbreviations

<h2>The pathophysiology of thrombotic thrombocytopenic purpura (TTP)</h2>
<h3>TTP is characterized by potentially fatal systemic microthrombi<sup>1,2</sup></h3>
<p>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.<sup>1</sup></p>
<p>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.<sup>2</sup></p>
<p data-font="legal">ADAMTS13=a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13.</p>
<h4>TTP pathophysiology</h4>
<p>An in-depth exploration of the causes of TTP and the severe consequences of the disease.</p>

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

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 aTTP<sup>2</sup></h3>

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

<h4 style="text-align: center;">ADAMTS13 deficiency causes&nbsp;uncleaved ULvWF</h4>
<p style="text-align: center;">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.</p>

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

<h3>Thrombotic Thrombocytopenic Purpura<sup>2,3</sup></h3>

<p data-font="legal">Adapted from Joly B et al. Blood 2017 and Saad J &amp; Schoenberger L 2018.</p>

<h2>Formation of microthrombi causes<sup>2</sup></h2>

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

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

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

<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><span style="color:#ffffff;"><strong>Platelet aggregation leads to microthrombi formation, which can have fatal consequences.<sup>1,2</sup></strong></span></h4></td>
  </tr>
 </tbody>
</table>

<h2>Signs and symptoms of aTTP</h2>
<p><strong>The symptoms of aTTP are driven by microthrombi, which are unpredictable and potentially fatal<sup>1,2</sup></strong></p>
<p>Microthrombi can have serious acute and chronic consequences in TTP—putting patients at risk for devastating effects and death without urgent treatment.</p>

<h3 style="text-align: center;">Microthrombi can occur in any organ with microvessels, but the most commonly affected are<sup>3</sup></h3>

<p data-font="legal">Tissue and organ damage resulting from ischemia leads to increased levels of lactate dehydrogenase (LDH), troponins (heart), and creatinine (kidney).¹,⁴</p>

<h2>Signs and symptoms of acquired thrombotic thrombocytopenic purpura (aTTP) include<sup>1,4,5</sup></h2>

<p>&nbsp;<strong>of TTP episodes result in ischemia due to platelet aggregation in the microcirculation of the brain.<sup>3</sup></strong></p>

<h2>The consequences of microthrombi can be severe, with TTP potentially resulting in acute thromboembolic events such as<sup>1,2,4</sup></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. <sup>1,2</sup>

<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>

<p data-font="legal"><strong>*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</strong></p>
<h2>All-cause death: All patients vs patients eligible for ≥3 years of follow-up</h2>

<p data-font="legal"><strong>*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.</strong></p>
<p data-font="legal"><strong>**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).</strong></p>
<h2>Post-hoc analysis: All-cause death by baseline LDL-C subgroups</h2>

<p><strong>Relative risk reduction: Pinteraction=0.12</strong></p>
<p><strong>Absolute risk reduction: Pinteraction=0.005</strong></p>
<p data-font="legal"><strong>*Based on cumulative incidence, alirocumab is associated with lower all-cause death as compared to placebo</strong></p>
<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>

Reference

Odyssey outcomes - mortality

DYSLIPIDEMIA

CARDIOLOGY

<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>
<p>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</p>

<h2>Objective</h2>
<p>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.</p>

<h2>Endpoints</h2>
<p>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.</p>

<h2>Methods</h2>
<p>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</p>
<p>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.</p>

<h2>Results</h2>
<p>At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycemia.</p>
<p>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).</p>

<h2>Conclusion</h2>
<p>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.</p>

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>
<p>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</p>
<h2>Objective</h2>
<p>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.</p>
<h2>Methods</h2>
<p>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.</p>
<p>Participants were randomly assigned (1:1) to receive alirocumab 75mg or matching placebo subcutaneously every 2 weeks.</p>
<h2>Endpoints</h2>
<p>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.</p>
<h2>Results</h2>
<p>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.</p>
<p>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).</p>
<h2>Conclusion</h2>
<p>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.</p>

Odyssey outcomes - CVOT mortality sub-analysis

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

<h2>CABG Sub-analysis overview</h2>
<h3>Study Design</h3>
<ul>
 <li>Prespecified analysis</li>
 <li>Patients were categorized by coronary artery bypass graft (CABG) status: 
  <ul>
   <li>No CABG (n=16,896)</li>
   <li>CABG after the index ACS but before randomization (index CABG; n=1,025, including n=44 with prior CABG), or</li>
   <li>CABG prior to the index ACS (prior CABG; n=1 ,003)</li>
  </ul></li>
 <li>The primary composite endpoint of MACE encompassed CHD death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization 
  <ul>
   <li>The secondary endpoint was all-cause death</li>
  </ul></li>
</ul>
<h2>Baseline demographics and index events</h2>
<table align="center" border="1" cellpadding="10" cellspacing="1">
 <tbody>
  <tr>
   <td style="background-color: rgb(244, 242, 247); width: 39%;">
    <p><strong>No CABG (n=16,896)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>Index CABG (n=1,025)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>Prior CABG (n=1,003)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>P-value</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 13%;">&nbsp;</td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Age, years, median (Q1, Q3)</p></td>
   <td style="width: 16%;">
    <p>58 (51, 65)</p></td>
   <td style="width: 16%;">
    <p>60 (53, 65)</p></td>
   <td style="width: 16%;">
    <p>63 (57, 70)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Female, % (n)</p></td>
   <td style="width: 16%;">
    <p>25.8 (4,354)</p></td>
   <td style="width: 16%;">
    <p>20.6 (211)</p></td>
   <td style="width: 16%;">
    <p>19.6 (197)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Body mass index, kg/m<sup>2</sup>, median (Q1, Q3)</p></td>
   <td style="width: 16%;">
    <p>28 (25, 31)</p></td>
   <td style="width: 16%;">
    <p>28 (25, 31)</p></td>
   <td style="width: 16%;">
    <p>29 (26, 32)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Region, % (n)</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Western Europe</p></td>
   <td style="width: 16%;">
    <p>22.3 (3,767)</p></td>
   <td style="width: 16%;">
    <p>22.4 (230)</p></td>
   <td style="width: 16%;">
    <p>17.7 (178)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Eastern Europe</p></td>
   <td style="width: 16%;">
    <p>29.9 (5,049)</p></td>
   <td style="width: 16%;">
    <p>17.6 (180)</p></td>
   <td style="width: 16%;">
    <p>20.7 (208)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>North America</p></td>
   <td style="width: 16%;">
    <p>13.5 (2,273)</p></td>
   <td style="width: 16%;">
    <p>24.1 (247)</p></td>
   <td style="width: 16%;">
    <p>35.0 (351)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>South America</p></td>
   <td style="width: 16%;">
    <p>13.6 (2,293)</p></td>
   <td style="width: 16%;">
    <p>17.6 (180)</p></td>
   <td style="width: 16%;">
    <p>11.5 (115)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Asia</p></td>
   <td style="width: 16%;">
    <p>13.0 (2,196)</p></td>
   <td style="width: 16%;">
    <p>5.5 (56)</p></td>
   <td style="width: 16%;">
    <p>4.1 (41)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Rest of the world</p></td>
   <td style="width: 16%;">
    <p>7.8 (1,318)</p></td>
   <td style="width: 16%;">
    <p>12.9 (132)</p></td>
   <td style="width: 16%;">
    <p>11.0 (110)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Index event, % (n)</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>NSTEMI</p></td>
   <td style="width: 16%;">
    <p>46.9 (7,913)</p></td>
   <td style="width: 16%;">
    <p>59.8 (612)</p></td>
   <td style="width: 16%;">
    <p>64.9 (650)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>STEMI</p></td>
   <td style="width: 16%;">
    <p>36.5 (6,156)</p></td>
   <td style="width: 16%;">
    <p>20.9 (214)</p></td>
   <td style="width: 16%;">
    <p>16.6 (166)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Unstable angina</p></td>
   <td style="width: 16%;">
    <p>16.6 (2,798)</p></td>
   <td style="width: 16%;">
    <p>19.3 (198)</p></td>
   <td style="width: 16%;">
    <p>18.6 (186)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Time from index event to randomization, months, median (Q1, Q3)</p></td>
   <td style="width: 16%;">
    <p>2.6 (1.7, 4.2)</p></td>
   <td style="width: 16%;">
    <p>3.8 (2.7, 6.8)</p></td>
   <td style="width: 16%;">
    <p>2.5 (1.7, 4.1)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
 </tbody>
</table>

<h2>Lipid-Lowering Therapy at Randomization and Baseline Laboratory Parameters</h2>
<table align="center" border="1" cellpadding="10" cellspacing="1">
 <tbody>
  <tr>
   <td style="background-color: rgb(244, 242, 247); width: 39%;">
    <p><strong>No CABG (n=16,896)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>Index CABG (n=1,025)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>Prior CABG (n=1,003)</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 16%;">
    <p><strong>P-value</strong></p></td>
   <td style="background-color: rgb(244, 242, 247); width: 13%;">&nbsp;</td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Lipid-lowering therapy at randomization, % (n)</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>High-dose atorvastatin or rosuvastatin</p></td>
   <td style="width: 16%;">
    <p>89.2 (15,077)</p></td>
   <td style="width: 16%;">
    <p>87.8 (900)</p></td>
   <td style="width: 16%;">
    <p>83.2 (834)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Other lipid-lowering therapy<sup>3</sup></p></td>
   <td style="width: 16%;">
    <p>10.0 (1,690)</p></td>
   <td style="width: 16%;">
    <p>10.4 (107)</p></td>
   <td style="width: 16%;">
    <p>13.8 (138)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>No lipid-lowering therapy</p></td>
   <td style="width: 16%;">
    <p>0.8 (129)</p></td>
   <td style="width: 16%;">
    <p>1.8 (18)</p></td>
   <td style="width: 16%;">
    <p>3.1 (31)</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Lipid measurements, mg/dL, median (Q1, Q3), unless stated</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 16%;">
    <p>&nbsp;</p></td>
   <td style="width: 13%;">
    <p>&nbsp;</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>LDL-C</p></td>
   <td style="width: 16%;">
    <p>86 (73, 103)</p></td>
   <td style="width: 16%;">
    <p>87 (74, 107)</p></td>
   <td style="width: 16%;">
    <p>94 (78, 116)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>LDL-C≥100 mg/dL,% (n)</p></td>
   <td style="width: 16%;">
    <p>28.9 (4,878)</p></td>
   <td style="width: 16%;">
    <p>32.5 (333)</p></td>
   <td style="width: 16%;">
    <p>41.7 (418)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>HDL-C</p></td>
   <td style="width: 16%;">
    <p>42 (36, 50)</p></td>
   <td style="width: 16%;">
    <p>42 (36, 50)</p></td>
   <td style="width: 16%;">
    <p>42 (35, 50)</p></td>
   <td style="width: 13%;">
    <p>0.0166</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Non-HDL-C</p></td>
   <td style="width: 16%;">
    <p>114 (99, 136)</p></td>
   <td style="width: 16%;">
    <p>117 (102, 140)</p></td>
   <td style="width: 16%;">
    <p>126 (107, 153)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Triglicerides</p></td>
   <td style="width: 16%;">
    <p>128 (94, 181)</p></td>
   <td style="width: 16%;">
    <p>137 (98, 192)</p></td>
   <td style="width: 16%;">
    <p>139 (102, 195)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Apoliproprotein B</p></td>
   <td style="width: 16%;">
    <p>79 (69, 92)</p></td>
   <td style="width: 16%;">
    <p>82 (70, 96)</p></td>
   <td style="width: 16%;">
    <p>85 (75, 103)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Lipoprotein(a)</p></td>
   <td style="width: 16%;">
    <p>20.3 (6.6, 58.1)</p></td>
   <td style="width: 16%;">
    <p>27.8 (7.5, 69.0)</p></td>
   <td style="width: 16%;">
    <p>33.2 (8.1, 79.9)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
  <tr>
   <td style="width: 39%;">
    <p>Estimated GFR &lt;60 mL/min per 1.73 m<sup>2</sup>, % (n)</p></td>
   <td style="width: 16%;">
    <p>12.7 (2138)</p></td>
   <td style="width: 16%;">
    <p>13.8 (141)</p></td>
   <td style="width: 16%;">
    <p>25.9 (260)</p></td>
   <td style="width: 13%;">
    <p>&lt;0.0001</p></td>
  </tr>
 </tbody>
</table>
<p data-font="legal">ᵃ low-/moderate-dose atorvastatin/rosuvastatin, other statin, any lipid-lowering therapy other than statin.</p>
<h2>Effect of Alirocumab in patients with ACS, Elevated Atherogenic Lipoproteins and Prior CABG</h2>

<p data-font="legal">ᵃ index CABG is CABG between the index ACS event and randomization (including 44 patients with prior CABG);<br>
  ᵇ Prior CABG is CABG prior to the index ACS event. HRs reflect stratification by geographic region</p>
<h2>CABG Sub-analysis Conclusions</h2>
<ul>
 <li>In this sub-analysis, it was observed that, in a population that has not been fully investigated with regards to the effect of LDL-C lowering therapies, the addition of alirocumab to patients with prior CABG, recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy was associated with consistent relative but greater ARR in MACE and death when compared to patients with an index or no CABG</li>
</ul>

Odyssey outcomes - CABG results

<p><strong>Alirocumab and Cardiovascular outcomes after Acute Coronary Syndrome.</strong></p>
<p>Gregory G Schwartz, P Gabriel Steg, Michael Szarek, Deepak L Bhatt, Vera A Bittner, Rafael Diaz, Jay M Edelberg, Shaun G Goodman, Corinne Hanotin, Robert A Harrington, J Wouter Jukema, Guillaume Lecorps, Kenneth W Mahaffey, Angèle Moryusef, Robert Pordy, Kirby Quintero, Matthew T Roe, William J Sasiela, Jean-François Tamby, Pierluigi Tricoci, Harvey D White, Andreas M Zeiher, Odyssey Outcomes Committees and Investigators</p>
<h2>Objective</h2>
<p>The aim of this study is to test the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, would result in a lower risk of recurrent ischemic cardiovascular events than placebo among patients who had an acute coronary syndrome within the preceding 1 to 12 months and who have levels of atherogenic lipoproteins that exceed specified thresholds despite statin therapy at a high-intensity dose or at the maximum tolerated dose.</p>
<h2>Endpoints</h2>
<p>The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.</p>
<p>Prespecified main secondary end points were any coronary heart disease event (death from coronary heart disease, nonfatal myocardial infarction, unstable angina requiring hospitalization, or an ischemia-driven coronary revascularization procedure); major coronary heart disease event (death from coronary heart disease or nonfatal myocardial infarction); any cardiovascular event (death from cardiovascular causes, nonfatal ischemic stroke, nonfatal myocardial infarction, unstable angina requiring hospitalization, or an ischemia-driven coronary revascularization procedure); a composite of death from any cause, nonfatal myocardial infarction, or nonfatal ischemic stroke; death from coronary heart disease; death from cardiovascular causes; and death from any cause.</p>
<h2>Methods</h2>
<p>A multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non−high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose.</p>
<p>Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter).</p>
<h2>Results</h2>
<p>The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P&lt;0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level.</p>
<p>Among the main secondary end points, the risks of any coronary heart disease event, major coronary heart disease events, any cardiovascular event, and a composite of death from any cause, nonfatal myocardial infarction, or nonfatal ischemic stroke were lower among patients treated with alirocumab than among those who received placebo. A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98).</p>
<p>The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).</p>
<h2>Conclusion</h2>
<p>Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo.</p>

NEJM Odyssey outcomes

Key Learnings in Dyslipidemia by Prof. Kausik Ray - 2021 EAS Congress

<p>Acquire profound insights into the realm of Dyslipidemia through the discerning perspective of Prof. Kausik Ray, the Director of the Imperial Center of Cardiovascular Disease Prevention and Deputy Director of the Imperial Clinical Trial Unit at Imperial College London. Prof. Ray offers a comprehensive review of the key takeaways from the 2021 EAS Congress.</p>
<p>Engage in in-depth conversations and analysis surrounding this vital subject matter. Join Prof. Ray in delving into the substantial findings unveiled during this enlightening event, ensuring you remain in the loop of the latest developments in Dyslipidemia management.</p>

<h2>Odyssey Outcomes: Addition of PCSK9i to background Statin therapy further reduces MACE.</h2>
<h3>Study Design¹</h3>

<h2>Major Primary endpoints¹</h2>
<p>The primary endpoint was a composite of:</p>
<ul>
 <li>Death from coronary heart disease</li>
 <li>Nonfatal myocardial infarction</li>
 <li>Fatal or nonfatal ischemic stroke</li>
 <li>Unstable angina requiring hospitalization.</li>
</ul>
<h2>Major Secondary efficacy Endpoints²</h2>
<p>Tested in the following hierarchical sequence:</p>
<ul>
 <li>CHD event: CHD death, nonfatal MI, unstable angina requiring hospitalization, or ischaemia-driven coronary revascularization*</li>
 <li>Major CHD event: CHD death or nonfatal MI</li>
 <li>CV event: CV death, nonfatal CHD event, or nonfatal ischaemic stroke</li>
 <li>All-cause death, nonfatal MI, nonfatal ischaemic stroke</li>
 <li>CHD death</li>
 <li>CV death</li>
 <li>All-cause death</li>
</ul>
<p data-font="legal">*Revascularization performed because of recurrent ACS, new or progressive symptoms of myocardial ischemia or new or progressive abnormalities on functional testing, except revascularization due to restenosis at a prior coronary intervention site.</p>
<h2>Odyssey Outcomes: Addition of PCSK9i to background Statin therapy further reduces MACE</h2>

<p>Safety: Incidence or adverse events and laboratory abnormalities was similar in the alirocumab group and the placebo group, apart from local injection-site reaction (3.8% in alirocumab group vs 2.1% in the placebo group, p&lt;0.001).</p>
<p data-font="legal">ᵃ Primary efficacy endpoint (a composite of death from CHD, nonfatal MI, fatal or nonfatal ischaemic stroke, or unstable angina requiring hospitalization)</p>

<h2>Primary MACE, All-cause death and safety</h2>

<h2>Safety</h2>
<p>Similar incidence of adverse events and laboratory abnormalities in the alirocumab group and the placebo group, except for local injection-site reactions (3 .8% in the alirocumab group vs 2.1% in the placebo group, p&lt;0.001)¹</p>
<p data-font="legal">*Nominal p-value; ᵃBased on cumulative incidence; bp-interaction value for ARR &lt;0.001 in post-hoc analysis</p>

<p data-font="legal">*Nominal p-value<br>
  †Based on cumulative incidence</p>

<h2>Primary Analysis Conclusions¹</h2>
<ul>
 <li>The primary results show that, compared with placebo in patients with recent ACS, alirocumab 75 or 150 mg SC twice a week targeting LDL-C levels 25-50 mg/dl reduced MACE, MI*, ischemic stroke* and was associated with a lower rate of all-cause death</li>
 <li>Among patients with ACS and baseline LDL-C &gt;100 mg/dl, alirocumab was well tolerated, reduced MACE by 24% (absolute risk reduction [ARR] 3.4%), and was associated with a lower rate of all-cause death compared with placebo</li>
</ul>
<p data-font="legal">*Nominally significant as per hierarchical testing.</p>

Odyssey outcomes

<h2>Main Takeaway</h2>
<p><strong>The rate of prescription of PCSK9i therapy was below expectations during the first year of availability</strong>&nbsp;in patients from the Tuscany region who had a prior CV event or had a comorbidity that increases CV risk</p>
<p>During first 6 months of follow-up,&nbsp;<strong>adherence and persistence to PCSK9i therapy were very satisfying</strong>, highlighting good tolerance and treatment compliance</p>
<h2>Why This Matters</h2>
<p>Italian Medicines Agency follows strict reimbursement criteria imposing a potential barrier to PCSK9i access, and this could have generated inequalities in the prescribing governance across Italian regions</p>
<h2>Study Design</h2>
<p>This Italian, real-world study included 269 patients from 26 specialized centers in Tusc any region who had:</p>
<ul>
 <li>a prior CV event or had a comorbidity that increases CV risk</li>
 <li>received at least one PCSK9i prescription (evolocumab or alirocumab) from July 2017 to June 2018</li>
</ul>
<p><strong>Lipid-lowering therapy (LLT) prescriptions</strong>&nbsp;in the 6 months before the index date (date of first PCSK9i dispensing) were analyzed based on the outpatient prescription database retrieved from the healthcare administrative databases</p>
<p><strong>Key inclusion criteria:</strong></p>
<ul>
 <li>adherence (proportion of days covered [PDC])</li>
 <li>persistence (absence of a gap longer than 30 days between end of dispensing duration and new dispensing period or end of follow-up)</li>
 <li>switch between different PCSK9is</li>
</ul>
<h2>Key Results</h2>
<h3>Patient population</h3>
<ul>
 <li>Overall, 269 new users of PCSK9i were included in the study: 
  <ul>
   <li>mean age = 59.1 years</li>
   <li>males = 71.0%</li>
   <li>primary prevention (N = 80), secondary prevention (N = 189)</li>
   <li>evolocumab (N = 176), alirocumab (N = 93)</li>
   <li>≥ 1 clinical condition increasing CV risk (N = 184) (most common: familial hypercholesterolemia (N = 144), diabetes mellitus (N = 66)</li>
  </ul></li>
 <li>The rate of PCSK9i prescription was&nbsp;<strong>7.2 per 100,000 inhabitants</strong></li>
 <li>In 6 months prior to first PCSK9i dispensing period,&nbsp;<strong>61.3% of the patients received at least one prescription of LLT included in reimbursement criteria</strong>&nbsp;(ezetimibe with/without high-intensity statin), whereas 16.4% of the patients received other LLTs and 22.3% of the patients had no LLT recorded</li>
</ul>
<h3>Outcomes</h3>
<ul>
 <li>Adherence:&nbsp;<strong>More than 80% of patients were adherent to therapy</strong>&nbsp;(PDC ≥75%) 
  <ul>
   <li>Similar trend for adherence to therapy was observed for evolocumab (80.6%) and alirocumab (79.1%)</li>
  </ul></li>
 <li>Persistence: During follow-up,&nbsp;<strong>73.3% of PCSK9i users</strong>&nbsp;(72.6% for evolocumab and 74.7% for alirocumab)&nbsp;<strong>were persistent to therapy for 6 months</strong>
  <ul>
   <li>Following a PCSK9i discontinuation, 19.2% of patients restarted therapy (primary vs secondary prevention: 20.6% vs 16.5%)</li>
  </ul></li>
 <li>Switch:&nbsp;<strong>Only one patient switched from evolocumab to alirocumab</strong></li>
</ul>
<h2>Limitations</h2>
<ul>
 <li>Lack of clinical information like LDL-C levels or statin intolerance did not permit to confirm the precise fulfilment of reimbursement criteria</li>
 <li>Enrollment of some subjects in the study post participation in a clinical trial could have resulted in misclassification of these participants as “new PCSK9i users”</li>
 <li>Adherence and persistence to PCSK9i therapy was evaluated for a short period</li>
</ul>
<ul>
</ul>

Italian real-world analysis on management and pattern of PCSK9 inhibitor use in the first six months of treatment

Italian real-world analysis for PCSK9 inhibitors new users

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