scholarly journals Pooled safety and efficacy of inclisiran in patients with statin intolerance (ORION-10 and ORION-11)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R.S Wright ◽  
D Kallend ◽  
F.J Raal ◽  
R Stoekenbroek ◽  
W Koenig ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Therapeutic Option ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Private Company ◽  
Phase 3 ◽  
Absolute Reduction ◽  
Secondary Endpoints

Abstract Introduction Statin-associated side effects prevent a substantial proportion of patients from being adequately treated with statin therapy and achieving adequate LDL-C reductions. Phase 3 trials showed that inclisiran, a new siRNA, durably lowers LDL-C by ≥50% on top of maximally tolerated statin therapy. Purpose To evaluate inclisiran's tolerability and LDL-C lowering effects among individuals who were not receiving statin therapy mainly because of statin intolerance. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) with LDL-C >70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. The primary efficacy endpoints were % change in LDL-C from baseline to Day 510 and time adjusted % change in LDL-C from baseline after Day 90 and up to Day 540. Absolute LDL-C reductions were secondary endpoints. This analysis included individuals who were not on statin therapy at baseline. Results The trials included 252 (7.9% of the pooled trial populations; mean age 68; male 62%; lipid-lowering therapy 28%). AE rates and LDL-C reductions are shown in the Table. Overall, 12 (4.7%) patients had myalgia (4.8% in the inclisiran groups, 4.7% in the placebo groups). There were 8 discontinuations in the inclisiran groups (6.5%) and 3 in the placebo groups (2.3%). The placebo-adjusted mean reduction in LDL-C at Day 510 was 45.8%, an absolute reduction of 68.0 mg/dL (p<0.0001). Conclusion Among statin intolerant individuals in ORION-10 and 11, inclisiran potently and durably lowered LDL-C with an adverse event profile comparable to placebo. Inclisiran may represent a new and potent therapeutic option for patients with elevated LDL-C unable to tolerate statins. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

scholarly journals What is the potential cardiovascular risk reduction associated with achieving LDL-C levels recommended in the ESC/EAS guidelines for very high-risk patients? Data from 18 European countries

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
S Bray ◽  
A.L Catapano ◽  
N Poulter ◽  
G Villa
Keyword(s):  
High Risk ◽  
Risk Reduction ◽  
Absolute Risk ◽  
European Countries ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Cardiovascular Risk Reduction ◽  
Private Company ◽  
Very High

Abstract Background/Introduction For patients at very-high risk of cardiovascular (CV) events, the 2016 ESC/EAS dyslipidaemia guidelines recommended lipid-lowering therapy (LLT) to achieve an LDL-C level below 70 mg/dL. This was lowered to an LDL-C level below 55 mg/dL in the 2019 guidelines. Purpose To assess: 1) the risk profile of European patients with established atherosclerotic CV disease (ASCVD) receiving LLT; and 2) the treatment gap between the estimated risk and the population benefits if all patients were to achieve LDL-C levels of 70 mg/dL and 55 mg/dL. Methods We used data from Da Vinci, an observational cross-sectional study conducted across 18 European countries. Data were collected at a single visit between June 2017 and November 2018, for consented adults who had received any LLT in the prior 12 months and had an LDL-C measurement in the prior 14 months. LDL-C level was assessed at least 28 days after starting the most recent LLT (stabilised LLT). For each patient with established ASCVD receiving stabilised LLT, we: 1) calculated their absolute LDL-C reduction required to achieve LDL-C levels of 70 mg/dL and 55 mg/dL; 2) predicted their 10-year CV risk using the REACH score based on demographic and medical history; 3) simulated their relative risk reduction (RRR) by randomly sampling from the probability distribution of the rate ratio per 38.7 mg/dL (1 mmol/L) estimated by the Cholesterol Treatment Trialists Collaboration meta-analysis; and 4) calculated their absolute risk reduction (ARR) achieved by meeting LDL-C levels of 70 mg/dL and 55 mg/dL. Results A total of 2039 patients with established ASCVD were included in the analysis. Mean (SD) LDL-C was 83.1 (35.2) mg/dL. 40.4% and 19.3% of patients achieved LDL-C levels of 70 mg/dL and 55 mg/dL, respectively. Mean (SD) 10-year CV risk calculated using the REACH score was 36.3% (15.4%). Mean absolute LDL-C reductions of 19.6 mg/dL and 30.4 mg/dL were needed to reach LDL-C levels of 70 mg/dL and 55 mg/dL, respectively. When adjusted for the LDL-C reduction required to achieve an LDL-C level of 70 mg/dL, mean ARR was 3.0%, leaving a mean (SD) residual 10-year CV risk of 33.3% (15.5%). When adjusted for the LDL-C reduction required to achieve an LDL-C level of 55 mg/dL, mean ARR was 4.6%, leaving a mean (SD) residual 10-year CV risk of 31.7% (15.2%). Conclusion(s) In a contemporary European cohort with ASCVD receiving LLT, the 10-year risk of CV events is high and many patients do not achieve LDL-C levels of 55 mg/dL or even of 70 mg/dL. Moreover, even if all patients were to achieve recommended LDL-C levels, they would still remain at a high residual risk of CV events. These data suggest these patients require even more intensive LLT. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen

Do European patients with peripeheral arterial disease receive optimal lipid lowering therapy and achieve LDL-C goals? Results from the DA VINCI study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
M Feudjo Tepie ◽  
A.L Catapano ◽  
P Giovas ◽  
S Bray ◽  
...  
Keyword(s):  
Da Vinci ◽  
Arterial Disease ◽  
Lipid Lowering ◽  
Moderate Intensity ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Private Company ◽  
Cerebral Disease ◽  
Study Visit ◽  
Lowering Therapy

Abstract Background 2016 and 2019 EAS/ESC dyslipidemia guidelines recommend lipid lowering therapy (LLT) to reduce LDL-C in patients with peripheral arterial disease (PAD) with or without established cardiovascular (CV) disease, and recommend target LDL-C goals based on individual CV risk. Data regarding the implementation of these guidelines in clinical practice across Europe is currently lacking. Purpose Describe LLT and achievement of the target LDL-C goals recommended in EAS/ESC dyslipidemia guidelines in patients with PAD. Methods The cross-sectional Da Vinci study enrolled consenting adults who had received LLT in the 12 months prior to the study visit and had at least one LDL-C measurement in the 14 months prior to the study visit, seen in a primary or secondary care setting across 18 European countries. Patients with coronary, peripheral and cerebral disease were enrolled at a ratio of 1:2:2. FH patients with prior CV events were excluded. Data were collected from medical records at a single visit between Jun '17–Nov '18, including LLT and most recent LDL-C. Primary outcome was LDL-C goal attainment ≥28 days after starting most recent LLT (treatment-stabilised LLT). Results Of 5888 patients enrolled, 2794 met our definition of atherosclerotic cardiovascular disease (ASCVD). Of these ASCVD patients, 1036 (37%) had PAD. 31% (323/1036) of PAD patients were female and mean (SD) age was 69 (9.4) years. Concomitant CV risk factors included diabetes mellitus (473/1036 patients [46%]), hypertension (809/1036 [78%]) and smoking (794/1036 [77%]). 26% (271/1036) of patients with PAD also had coronary vascular disease and 12% (122/1036) also had cerebrovascular disease. At the visit date, approximately half (497/1036 [48%]) of all PAD patients were receiving moderate intensity statins and 41% (421/1036) were receiving high intensity statins. 818 (73%) of the PAD patients had a treatment-stabilised LDL-C measurement (median, 2.20 mmol/L), of whom 40% (326/818) achieved the 2016 EAS/ESC LDL-C goal of 1.8 mmol/L and only 19% (159/818) achieved the 2019 goal of 1.4mmol/L. Conclusions European patients with PAD are not treated as per EAS/ESC recommendations, with a large proportion receiving suboptimal LLT and fewer than half achieving target LDL-C levels. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen

scholarly journals Alirocoumab: new perspectives of lipid-lowering therapy

2017 ◽  
Vol 89 (12) ◽  
pp. 114-121
Author(s):  
Zh D Kobalava ◽  
S V Villevalde ◽  
M A Vorobyeva
Keyword(s):  
Statin Therapy ◽  
Ldl Cholesterol ◽  
Human Monoclonal Antibody ◽  
Secondary Analysis ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Good Tolerability ◽  
Long Term Study

Alirocoumab (Praluent) is a fully human monoclonal antibody against proprotein covertase subtilisin/kexin type 9 (PCSK9). The data of ODYSSEY Phases II and III clinical trials demonstrate the high efficacy of alirocoumab in lowering the level of low-density lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia, with a considerable advantage over control groups (placebo, ezetimibe or modified statin therapy) in both monotherapy and combination therapy with statins and other lipid-lowering agents. Alirocoumab provides additional lipid-lowering effects against other atherogenic fractions of cholesterol, including non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein (a). The agent show high safety and good tolerability and it can be considered as the drug of choice for patients who have not reached their target LDL cholesterol levels after statin therapy and have statin intolerance and familial heterozygous hypercholesterolemia. There are now the preliminary results of a secondary analysis of data from the ODYSSEY LONG TERM study, suggesting that alirocoumab therapy may be accompanied by a lower risk of cardiovascular events. The final results will be provided after the data of a study of cardiovascular outcomes after therapy with alirocoumab versus placebo (ODYSSEY OUTCOMES) are published.

Abstract 14248: Efficacy and Safety of Bempedoic Acid in Patients Who Cannot Tolerate Statins: Pooled Analysis of 4 Phase 3 Clinical Trials

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ulrich Laufs ◽  
Maciej Banach ◽  
Harold E Bays ◽  
Alberico L Catapano ◽  
P Barton Duell ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Pooled Analysis ◽  
Lipid Lowering ◽  
Drug Discontinuation ◽  
Lipid Lowering Therapy ◽  
Efficacy And Safety ◽  
Statin Intolerance ◽  
Phase 3 ◽  
Additional Information

Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. BA has been shown to significantly lower LDL-C by a mean of ~18% in patients receiving background maximally tolerated statins and a mean of ~25% in patients with statin intolerance. Objective: Determine efficacy and safety of BA in statin-intolerant patients receiving no background statin therapy across 4 phase 3 clinical trials. Methods: Data were pooled from 4 randomized (2:1), placebo-controlled studies evaluating oral BA 180 mg once daily vs placebo for 12 to 52 weeks. Primary efficacy endpoint was LDL-C % change from baseline to week 12. Safety assessments included treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI), and laboratory values. For patients who reported SAMs, additional information around etiology and location were collected. Results: Of 3621 patients, 586 (394 BA; 192 placebo) reported intolerance to multiple statins because of SAMS or other AEs and received no statins during the studies. Mean baseline LDL-C was 148.7 mg/dL. After 12 weeks, BA significantly lowered LDL-C vs placebo (placebo-corrected, -26.5%; P < 0.001). Myalgia was the top reason for drug discontinuation, but was less common in the BA arm (17.7%) vs placebo (43.5%). CK > 5 х ULN was uncommon in both groups. Among AESIs (Table) , muscle disorders were reported by 12.7% (BA) vs 14.1% (placebo). Myalgia was less common with BA (4.6%) vs placebo (7.3%). Muscle spasms (4.1% vs 3.6%) and pain in extremity (3.3% vs 2.1%) were comparable between treatment groups. Muscular weakness was rare (0.5% BA, 1% placebo). Conclusion: Among the population of patients unable to use statins, BA significantly lowered LDL-C vs placebo without increasing muscle-related TEAEs. BA may be an appropriate lipid-lowering therapy for patients with hyperlipidemia who are statin intolerant.

scholarly journals Adverse effects of statin therapy: real evidence

2019 ◽  
Vol 10 (1) ◽  
pp. 51-61 ◽  
Author(s):  
Marina G. Bubnova
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Statin Therapy ◽  
Treatment Compliance ◽  
Lipid Lowering ◽  
Current View ◽  
Tolerability Profile ◽  
Lipid Lowering Therapy ◽  
Statin Intolerance ◽  
Good Tolerability

Aim. To provide a current view on the tolerability and safety of statin therapy. Materials and methods. The data of 73 scientific sources from Russian and foreign literature published within 1996-2018 are considered. Results. It is generally accepted that statins are first-line therapeutic agents for hypercholesterolemia and combined hyperlipidemia. Today there in growing evidence that lowering of low-density lipoprotein cholesterol levels prevents atherosclerotic diseases and reduces a risk of cardiovascular and overall mortality. Main issues of current statin therapy include a use of inadequate dosage for atherosclerotic diseases prevention, low treatment compliance and drug intolerance. In recent years the issue of statin intolerance has become of great importance. Criteria were proposed for determining an inability to tolerate statins, some experts suggest replacing definition of “statin intolerance” with the term “statin-associated side-effects”. Most discussed adverse effects due to statins include muscle-related symptoms (myalgia/myopathy), hepatotoxicity (hepatic hyperenzymemia) new-onset diabetes, dementia and cognitive impairment. Mechanisms of development of these adverse effects are still unclear. Certain factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were established. Some factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were identified. Occurrence of statin-associated side-effects depends on statin dose, a patient's age, gender, comorbidity and concomitant therapy. Many adverse effects of statins are drug class effect. At the same time each of statins has specific features of its structure, metabolism, drug interactions and pharmacokinetics. Pitavastatin belongs to the last generation of statins and it has distinct pharmacological features and neutral diabetogenic effects, etc. Risk of adverse effects due to statins is often exaggerated while benefit from the use of statins for preventing atherosclerotic diseases outweighs potential risks. Real occurrence of some adverse effects due to statin therapy requires additional evidence. Conclusion. Overall, statins have a good tolerability profile and are approved for use in the vast majority of patients who required lipid-lowering therapy.

Baseline triglycerides and non-HDL-C and apoB goal attainment in the ORION-10 and ORION-11 trials

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
D Kallend ◽  
F.J Raal ◽  
R Stoekenbroek ◽  
W Koenig ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Goal Attainment ◽  
Therapeutic Option ◽  
Funding Source ◽  
Private Company ◽  
Atherogenic Dyslipidaemia ◽  
Secondary Endpoints ◽  
Cv Disease ◽  
Total Burden ◽  
The Impact

Abstract Introduction Elevated triglyceride (TG) levels contribute to the total burden of circulating atherogenic lipoprotein levels and are associated with increased cardiovascular (CV) risk. LDL-C underestimates risk in patients with elevated TG. Therefore, 2019 ESC/EAS guidelines recommend apoB or non-HDL-C as secondary lipid goals for patients with TG &gt;150mg/dL. Purpose To assess the impact of inclisiran on apoB and non-HDL-C goal attainment across a range of TG levels among patients with atherosclerotic CV disease (ASCVD). Methods The ORION-10 and ORION-11 trials included 3178 patients with ASCVD and LDL-C &gt;70mg/dl despite maximally tolerated statins randomized to inclisiran or placebo (1:1). Pre-specified secondary endpoints were placebo-corrected changes in lipids at Day 510. For this analysis patients were stratified by TG quartiles at baseline within each trial. The proportion of individuals attaining apoB &lt;55 mg/dL or non-HDL-C &lt;70mg/dl within each trial were assessed across TG strata and the likelihood of goal attainment within TG strata assessed using logistic regression. Results In ORION-10, TG quartiles were ≤94, 94 to ≤128, 128 to ≤181 and &gt;181mg/dl respectively and in ORION-11 corresponding values were ≤101, 101 to ≤135, 135 to ≤183 and &gt;183mg/dl. As compared to placebo a significantly greater proportion of patients randomised to inclisiran attained apoB goals within each TG strata (Table). Similar results were observed for non-HDL-C. Conclusion Among patients with ASCVD on maximally tolerated statin and high TG levels, attainment of apoB and non-HDL-C secondary lipid targets was more likely with inclisiran than placebo. Inclisiran may be a useful therapeutic option for patients with atherogenic dyslipidaemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

Effect of bempedoic acid on uric acid and gout in 3621 patients with hypercholesterolemia: pooled analyses from phase 3 trials

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.K Ray ◽  
G.L Bakris ◽  
M Banach ◽  
A Catapano ◽  
P.B Duell ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Lipid Lowering ◽  
Funding Source ◽  
Lipid Lowering Therapy ◽  
Private Company ◽  
Anion Transporter ◽  
History Of

Abstract Background Bempedoic acid (BA), an oral ATP-citrate lyase inhibitor, significantly lowers low-density lipoprotein cholesterol levels in patients with hypercholesterolemia. In clinical trials of BA, small mean increases in uric acid have been reported. BA weakly inhibits organic anion transporter 2 (OAT2) in vitro, which may account for small elevations in serum uric acid. Purpose To assess uric acid levels and incidence of gout with BA treatment. Methods Data were pooled from 4 randomized (2:1), double-blind studies of BA (180 mg daily) vs placebo for 12 weeks to 52 weeks in patients with hypercholesterolemia on stable background lipid-lowering therapy. Safety assessments included adverse events of special interest (elevation in uric acid levels, gout) and laboratory assessments. Results A total of 2424 patients treated with BA and 1197 patients on placebo were included in this analysis. Mean (SD) baseline uric acid levels were 6.0 (1.4) mg/dL for both groups. History of gout was reported by 5.2% (127/2424) and 5.8% (69/1197) in the BA and placebo groups, respectively. At week 12, mean (SD) serum uric acid levels (% change from baseline) increased from baseline with BA treatment by 0.82 (0.97) mg/dL (14.8%) vs –0.02 (0.82) mg/dL (0.67%) for placebo. Elevations in serum uric acid levels typically occurred within the first 4 weeks of treatment, remained stable during treatment, and returned to baseline after treatment discontinuation. Gout was reported in 1.4% (BA) and 0.4% (placebo) of patients, and hyperuricemia was reported in 1.7% (BA) and 0.6% (placebo) of patients. Other potential clinical consequences of elevated uric acid levels (eg, events associated with nephrolithiasis), were similar between groups (0.7% vs 0.8%). In both groups, patients who reported gout during the studies were more likely to have a medical history of gout or elevated baseline uric acid levels (Table). Few patients discontinued treatment due to gout (n=1, &lt;0.1% [BA]) or uric acid increases (n=2, &lt;0.1% [BA]). Conclusion Mean increases in uric acid levels were small, remained stable while patients continued to receive treatment, were infrequently associated with AEs, and were reversible on discontinuation of BA Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

scholarly journals Acute arterial events across all vascular territories in the FOURIER trial

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Oyama ◽  
R Giugliano ◽  
M Tang ◽  
M Bonaca ◽  
J Saver ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Lipid Lowering ◽  
Acute Limb Ischemia ◽  
Lipid Lowering Therapy ◽  
Peripheral Vascular ◽  
Private Company ◽  
Pcsk9 Inhibitor ◽  
Vascular Beds ◽  
Pcsk9 Inhibition ◽  
Over Time

Abstract Background In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial, adding the PCSK9 inhibitor evolocumab to statin therapy reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Although atherosclerotic coronary, cerebrovascular, and peripheral vascular events share a related pathobiology, the effect of aggressive LDL-C lowering with PCSK9 inhibition on the risk of acute arterial events across all three vascular beds is not well-described. Purpose To assess the efficacy of evolocumab on acute arterial events in all vascular territories including coronary, cerebral, and peripheral vascular beds. Methods In the FOURIER trial, patients (n=27,564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). Acute arterial events were defined as a composite of coronary (coronary heart disease [CHD] death, myocardial infarction [MI], or urgent coronary revascularization), cerebrovascular (ischemic stroke, transient ischemic attack [TIA], or urgent cerebral revascularization), or peripheral vascular (acute limb ischemia, major amputation, or urgent peripheral revascularization) events. Cox proportional-hazard models were used to assess the efficacy of evolocumab on these outcomes. Landmark and total event analyses were also done. Results Of the 2,210 first acute arterial events occurring during follow-up, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced the risk of a first acute arterial event by 19% (HR 0.81, 95% CI 0.74–0.88; P&lt;0.001), with significant individual reductions in acute coronary (HR 0.83; 95% CI 0.75–0.91; P&lt;0.001), acute cerebrovascular (HR 0.77; 95% CI 0.65–0.92; P=0.004), and acute peripheral vascular (HR 0.58; 95% CI 0.38–0.88; P=0.01) events (Figure, top). The magnitude of the risk reduction with evolocumab tended to increase over time, with a 16% reduction (HR 0.84; 95% CI 0.75–0.96) in the first year followed by a 24% reduction (HR 0.76; 95% CI 0.67–0.85) thereafter (Figure, bottom). There were 3,780 total acute arterial events (first plus recurrent), with a 22% reduction with evolocumab (incidence rate ratio [RR] 0.78; 95% CI 0.70–0.87). Evolocumab prevented 496 total acute arterial events as compared to 222 first events. Conclusions The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced the risk of acute arterial events across all vascular territories with a robust effect over time. These findings indicate a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): The FOURIER trial was supported by Amgen.

scholarly journals Inter-individual variability in LDL-C reductions with inclisiran – data from ORION-10 and ORION-11

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R.S Wright ◽  
F.J Raal ◽  
D Kallend ◽  
R Stoekenbroek ◽  
W Koenig ◽  
...  
Keyword(s):  
Individual Variability ◽  
Funding Source ◽  
Percent Reduction ◽  
Private Company ◽  
Phase 3 ◽  
Novel Therapy ◽  
Pooled Data ◽  
Primary Endpoints ◽  
Average Change ◽  
Secondary Endpoints

Abstract Introduction Inclisiran, an investigational siRNA, has been shown to effectively and durably lower LDL-C in Phase 3 trials. Inter-individual variability in LDL-C reductions has been documented for statin therapy and ezetimibe. Purpose To evaluate the inter-individual variability in LDL-C lowering with inclisiran. Methods The Phase 3 ORION-10 and ORION-11 trials randomized patients with established ASCVD (or risk-equivalents) who had LDL-C &gt;70 mg/dl despite maximally tolerated statins to inclisiran or placebo (1:1). Inclisiran sodium 300 mg was administered s.c. at baseline, three months later, then every six months. Co-primary endpoints were the LDL-C reduction from baseline to Day 510 and the time adjusted average % change in LDL-C reduction after Day 90 and up to Day 540. Measures of response variability were pre-specified secondary endpoints. This analysis examines the inter-individual variability of LDL-C reductions at day 510 using pooled data from both trials. Results The analysis included 3178 individuals (92% on statins). At Day 90, 97% of inclisiran-treated patients had an LDL-C reduction. At Day 510, the median percent reduction in LDL-C levels from baseline was 57.3% in the inclisiran group (interquartile range, 44%-70%). An LDL-C reduction ≥50% was reached by 1359 (86.6%) inclisiran-treated patients versus 97 (6.2%) placebo patients at any visit (odds ratio [OR] 97.6, 95% confidence interval [CI] 76–126). An LDL-C reduction ≥30% was reached by 1523 (97.0%) inclisiran-treated patients versus 371 (23.7%) placebo patients (OR 104.5, 95% CI 76–143). At Day 510, 921 patients (65.1%) in the inclisiran group had a reduction ≥50% in LDL-C compared to 34 patients (2.4%) in the placebo group, and 1228 (86.8%) had a reduction ≥30% compared to 148 (10.5%), respectively. Among placebo-treated patients, there was a substantial proportion with notable increases in LDL-C at Day 510 (figure). Conclusion In Phase 3 trials, inclisiran on top of maximally tolerated statins provided reliable, consistent and durable reductions in LDL-C. A large percentage of subjects randomized to inclisiran achieved substantial reductions (&gt;50%) in LDL-C and nearly all achieved at least a 30% reduction suggesting inclisiran is potentially a promising novel therapy for patients needing sustained LDL-C reductions. Waterfall plot of pooled trials Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The Medicines Company

scholarly journals Lipoprotein(a) and Cardiovascular Outcomes after Revascularization of Carotid and Lower Limbs Arteries

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 257
Author(s):  
Marat V. Ezhov ◽  
Narek A. Tmoyan ◽  
Olga I. Afanasieva ◽  
Marina I. Afanasieva ◽  
Sergei N. Pokrovsky
Keyword(s):  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Cardiovascular Outcomes ◽  
Lower Limbs ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Cox Regression Analysis ◽  
Lipoprotein A ◽  
Secondary Endpoints

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

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