Köenig, Wolfgang

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.

Abstract Aims Patients with diabetes (DM) and metabolic syndrome (MS) have elevated risks for atherosclerotic cardiovascular disease (ASCVD). Aggressive LDL-C lowering reduces risks. Inclisiran, a new siRNA, lowers LDL-C and was evaluated in patients with Type 2 diabetes (DM), metabolic syndrome (MS) without DM or neither (N) in the ORION-10 trial. Methods ORION-10 was a double-blind, randomized, placebo controlled trial evaluating inclisiran in 1561 patients with ASCVD on maximally tolerated therapy for lowering LDL-C. 781 inclisiran (INC) participants and 780 placebo (P) patients received 1.5 mL SQ tx at Days 1, 90, then every 6 months until Day 540. We evaluated the time adjusted change in LDL-C from baseline after Days 90–540 in DM (n = 702), MS (n = 455) and N participants (n = 404). Results There were no differences in baseline demographics and background therapies between INC and P. Statins were utilized in 89.8% INC and 88.7% of P. High intensity statins were utilized in 67.2% of INC and 68.8% of P; ezetimibe in 10.2% of NC and 9.5% of P participants. INC reduced LDL-C by − 54.4% (−58.3, −50.6 95% CI) in DM, (P < 0.001), −58.6% (−62.3, −54.8), P < 0.001 in-MS and −56.0% (−60.2, −51.7), in N subjects P < 0.001 (see Figure). Conclusions Inclisiran potently and durably reduces LDL-C across patients with DM, MS and those with neither, demonstrating potent efficacy and durability across glycaemic categories. Inclisiran may also represent a potent LDL-C lowering treatment for those with DM and MS.

Abstract Background Patients (pts) with hyperlipidaemia and established cerebrovascular disease (CeVD) are at an increased risk of future strokes or other cardiovascular events.[1] In ischaemic stroke survivors, statins and inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) reduce recurrent cardiovascular events including stroke.[2–4] With guidelines increasingly advocating lower LDL-C goals, add-on lipid lowering therapies to statins may be needed. Inclisiran, a first-in-class small interfering RNA (siRNA) targeting PCSK9 messenger RNA, when added to maximally tolerated statin therapy, may provide further LDL-C lowering with a convenient, infrequent dosing schedule in pts with established CeVD. Purpose To assess efficacy and safety of inclisiran in pts with established CeVD. Methods Pts with HeFH, ASCVD or its risk equivalents from ORION-9 (NCT03397121]), ORION-10 (NCT03399370), and ORION-11 (NCT03400800) were randomised 1:1 to receive inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or placebo (pbo) at Days 1, 90 and 6-monthly thereafter to Day 540. This post hoc analysis included pts with established CeVD (ischaemic stroke, and/or carotid artery stenosis by angiography or ultrasound >70%, and/or prior percutaneous or surgical carotid artery revascularisation). Percentage LDL-C change from baseline to Day 510 and corresponding time-averaged percentage change from baseline after Day 90 to Day 540 were evaluated. Safety was assessed over 540 days. Results Of 202 pts with established CeVD, 110 and 92 received inclisiran and pbo, respectively. At baseline, 90.0% (99/110) of pts in inclisiran and 84.8% (78/92) in pbo group reported prior ischaemic stroke(s); others had carotid artery stenosis and/or carotid revascularisation (Table 1). Mean (95% CI) pbo-corrected LDL-C percentage change from baseline at Day 510 with inclisiran was −55.2% (−64.5 to −45.9); corresponding time-averaged change from baseline after Day 90 to Day 540 was −55.2% (−62.4 to −47.9) (P<0.0001 for each; Table 2). Treatment-emergent adverse event (TEAE) and treatment-emergent serious adverse event (TESAE) were more frequent in the inclisiran vs pbo group but were consistent with the overall pooled (N=3655) population of the combined trials. Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran (3.6% [4/110]) vs pbo (0% [0/92]), but none were severe. Percentage of pts with clinically relevant laboratory measurements was low and similar between treatment groups and consistent with the overall pooled population (Table 2). Conclusions In pts with established CeVD, a twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided sustained additional LDL-C reduction of ∼55%. A modest excess of mild/moderate TEAEs at the injection site were reported with inclisiran. The cardiovascular benefits of inclisiran among patients with established CeVD are being evaluated in ongoing trials. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland.

Abstract Background Approximately 25% of patients (pts) with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD), which involves ≥2 coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular (CV) events (MACE) and death.[1,2] Agents that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) resulted in reduced low-density lipoprotein cholesterol (LDL-C) concentration and MACE incidence in pts with PVD.[3,4] Inclisiran is a small interfering RNA (siRNA) agent targeting PCSK9 messenger RNA that provided effective and sustained reduction in LDL-C concentration and was well tolerated.[5] Purpose To describe the effect inclisiran versus placebo (pbo) in pts with and without PVD. Methods This was a post hoc analysis from the ORION-9 (NCT03397121), ORION-10 (NCT03399370) and ORION-11 (NCT03400800) trials. Pts with heterozygous familial hypercholesterolaemia, ASCVD or risk equivalents were randomised 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or pbo at baseline, Day 90, and 6-monthly thereafter. LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 and to Day 540 were evaluated by presence or absence of PVD (intention-to-treat population). Safety was assessed over 540 days (safety population). Results Of 3454 pts, 470 (13.6%) had PVD and 2984 (86.4%) did not. Baseline characteristics were generally balanced between treatment arms in both groups (Table 1). A greater proportion of pts with vs without PVD had CV risk factors at baseline. Mean LDL-C concentration at baseline was lower in pts with vs without PVD (Table 1). Mean (95% CI) pbo-corrected LDL-C percentage change from baseline to Day 510 with inclisiran was −48.9 (−55.6 to −42.2) in pts with PVD and −51.5 (−53.9 to −49.1) in pts without PVD (Table 2). Proportions of pts with treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events (TESAE) were similar between treatment arms irrespective of PVD status although reported TESAEs were numerically greater in both treatment arms for pts with PVD (Table 2). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo in both groups but all were mild or moderate (Table 2). Proportions of pts with clinically relevant laboratory measurements were low and similar between treatment arms for both groups (Table 2). Conclusions Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in pts, irrespective of their PVD status, with a safety profile similar to pbo, except for a modest excess of mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in pts with PVD, which was likely due to their more advanced disease. Since pts with PVD are at high risk of CV events, intensive LDL-C lowering may be beneficial to reduce this risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher ( P <0.001), and there were fewer women ( P =0.046) in the AF than in the non‐AF group. Left ventricular ejection fraction was significantly lower ( P =0.001), and cardiogenic shock was more often observed ( P <0.001) in the AF group. Both in‐hospital ( P <0.001) and long‐term mortality ( P <0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long‐term mortality (hazard ratio, 2.31; 95% CI, 1.50–3.55; P <0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in‐hospital and long‐term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in‐hospital and long‐term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01947621.

Introduction: The risk of major atherosclerotic CV events increases with age, as do comorbidities, polypharmacy, and greater vulnerability to adverse drug reactions/events, posing challenges in the treatment of dyslipidemia. Three Phase III placebo-controlled trials evaluated the efficacy and safety of inclisiran according to age. Objective: To assess the efficacy and safety of inclisiran in patients across age categories. Methods: Patients were categorized according to age: <65 years (not old), ≥65 and <75 years (old), or ≥75 years (very old). The co-primary endpoints were percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change from baseline after Day 90 up to Day 540. Efficacy and safety parameters were assessed over 18 months. Results: Of a total 3660 patients, 1737 [47.5%] were not old, 1431 [39.1%] were old, and 492 [13.4%] were very old. At baseline, the prevalence of comorbidities increased with age (not old, old, very old): stage 3 CKD (8.4%, 19.9%, 31.2%), hypertension (72.9%, 85.2%, 88.1%) and diabetes mellitus (32.2%, 40.0%, 38.0%), respectively. The placebo-corrected percentage change in LDL-C with inclisiran was similar across all ages: from baseline to Day 510 [–51.3% (not old), –49.9% (old), –51.0% (very old); P <0.0001 for all] and time-adjusted from baseline to Day 90 up to Day 540 [–49.6% (not old), –51.5% (old), –50.8% (very old); P <0.0001 for all]. Overall AE and SAE rates increased with age and were similar between both treatment arms in all groups, except for injection-site reactions that were higher with inclisiran vs placebo across all ages, and were more frequent in not old patients. CK levels >5x ULN were more frequently elevated in the not old category (Table). Conclusion: Inclisiran lowered LDL-C similarly across all ages with an acceptable safety profile. Inclisiran added to maximally tolerated statin therapy could be a safe option for older patients with ASCVD who need more intensive lipid-lowering treatment.

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.

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 &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. 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&lt;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

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

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