Citations

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— Aspirin is beneficial in the setting of atherosclerotic cardiovascular disease. There are limited data evaluating preoperative aspirin administration preceding coronary artery bypass grafting and associated postoperative outcomes. Methods and Results— Using prospectively collected data from 1636 consecutive patients undergoing first-time isolated coronary artery bypass surgery at our institution from January 2000 through December 2002, we evaluated the association between aspirin usage within the 5 days preceding coronary bypass surgery and risk of adverse in-hospital postoperative events. A logistic regression model, which included propensity scores, was used to adjust for remaining differences between groups. Overall, there were 36 deaths (2.2%) and 48 adverse cerebrovascular events (2.9%) in the postoperative hospitalization period. Patients receiving preoperative aspirin (n=1316) had significantly lower postoperative in-hospital mortality compared with those not receiving preoperative aspirin [1.7% versus 4.4%; adjusted odds ratio (OR), 0.34; 95% CI, 0.15 to 0.75; P =0.007]. Rates of postoperative cerebrovascular events were similar between groups (2.7% versus 3.8%; adjusted OR, 0.67; 95% CI, 0.32 to 1.50; P =0.31). Preoperative aspirin therapy was not associated with an increased risk of reoperation for bleeding (3.5% versus 3.4%; P =0.96) or requirement for postoperative blood product transfusion (adjusted OR, 1.17; 95% CI, 0.88 to 1.54; P =0.28). Conclusions— Aspirin usage within the 5 days preceding coronary artery bypass surgery is associated with a lower risk of postoperative in-hospital mortality and appears to be safe without an associated increased risk of reoperation for bleeding or need for blood product transfusion.

Background: The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. Results: CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. Conclusions: A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. Funding: There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.

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.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 ( ADCY9 ) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.