Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained ...reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol.
ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577.
Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7–44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1–41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm.
Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran.
Novartis Pharma.
Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of ...inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins.
This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% 95% confidence interval (CI): -52.8 to -34.6 with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site.
Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.
Abstract
Aims
Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, ...infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran.
Methods and results
The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: −0.5%; 500 mg: −1.8%; DD: 100 mg: 1.3%; 200 mg: −0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens.
Conclusion
In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
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.
We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data.
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.
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.
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.
To define the effect of a history of cancer on in-hospital and long-term mortality after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).
In ...this retrospective cohort study of 2346 patients with STEMI enrolled in the Mayo Clinic PCI registry from November 1, 2000, through October 31, 2010, we identified 261 patients (11.1%) with a history of cancer. The in-hospital and long-term outcomes (median follow-up, 6.2 years; interquartile range=4.3-8.5 years), including cardiac and noncardiac death and heart failure hospitalization, of these patients were compared with those of 1313 cancer-negative patients matched on age, sex, family history of coronary artery disease, and date of STEMI.
Patients with cancer had higher in-hospital noncardiac (1.9% vs 0.4%; P=.03) but similar cardiac (5.8% vs 4.6%; P=.37) mortality as matched controls. The group at highest acute mortality risk were those diagnosed as having cancer within 6 months before STEMI (hazard ratio HR=7.0; 95% CI, 1.4-34.4; P=.02). At 5 years, patients with cancer had similar cardiac mortality (4.2% vs 5.8%; HR=1.27; 95% CI, 0.77-2.10; P=.35) despite more heart failure hospitalizations (15% vs 10%; HR=1.72; 95% CI, 1.18-2.50; P=.01) but faced higher noncardiac mortality (30.0% vs 11.0%; HR=3.01; 95% CI, 2.33-3.88; P<.001) than controls, attributable solely to cancer-related deaths.
One in 10 patients in this contemporary registry of patients undergoing primary PCI for STEMI has a history of cancer. These patients have more than a 3 times higher acute in-hospital and long-term noncardiac mortality risk but no increased acute or long-term cardiac mortality risk with guideline-recommended cardiac care.
Nanette K. Wenger, MD ACCF/AHA Task Force Members Jeffrey L. Anderson, MD, FACC, FAHA, Chair; Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair; Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect; ...Nancy M. Albert, PhD, CCNS, CCRN; Mark A. Creager, MD, FACC, FAHA; David DeMets, PhD; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC; Judith S. Hochman, MD, FACC, FAHA; Frederick G. Kushner, MD, FACC, FAHA; E. Magnus Ohman, MD, FACC; William Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Table of Contents Developed in Collaboration With the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine Preamble (UPDATED)...e182 Introduction (UPDATED)...e184 Organization of Committee and Evidence Review (UPDATED)...e184 Document Review and Approval (UPDATED)...e185 Purpose of These Guidelines...e185 Overview of the Acute Coronary Syndromes...e186 Definition of Terms...e186 Pathogenesis of UA/NSTEMI...e186 Presentations of UA and NSTEMI...e189 Management Before UA/NSTEMI and Onset of UA/NSTEMI...e189 Identification of Patients at Risk of UA/NSTEMI...e189 Interventions to Reduce Risk of UA/NSTEMI...e190 Onset of UA/NSTEMI...e191 Recognition of Symptoms by Patient...e191 Silent and Unrecognized Events...e191 Initial Evaluation and Management...e191 Clinical Assessment...e191 Emergency Department or Outpatient Facility Presentation...e195 Questions to Be Addressed at the Initial Evaluation...e196 Early Risk Stratification...e196 Estimation of the Level of Risk...e198 Rationale for Risk Stratification...e198 History...e198 Anginal Symptoms and Anginal Equivalents...e198 Demographics and History in Diagnosis and Risk Stratification...e199 Estimation of Early Risk at Presentation...e200 Electrocardiogram...e202 Physical Examination...e203 Noncardiac Causes of Symptoms and Secondary Causes of Myocardial Ischemia...e204 Cardiac Biomarkers of Necrosis and the Redefinition of AMI...e204 Creatine Kinase-MB...e205 Cardiac Troponins...e205 Clinical Use...e205 Clinical Use of Marker Change Scores...e207 Bedside Testing for Cardiac Markers...e208 Myoglobin and CK-MB Subforms Compared With Troponins...e208 Summary Comparison of Biomarkers of Necrosis: Singly and in Combination...e208 Other Markers and Multimarker Approaches...e208 Ischemia...e208 Coagulation ...e209 Platelets...e209 Inflammation...e209 B-Type Natriuretic Peptides...e210 Immediate Management...e210 Chest Pain Units...e211 Discharge From ED or Chest Pain Unit...e212 Early Hospital Care...e213 Anti-Ischemic and Analgesic Therapy...e214 General Care...e215 Use of Anti-Ischemic Therapies...e215 Nitrates...e215 Morphine Sulfate...e217 Beta-Adrenergic Blockers...e217 Calcium Channel Blockers...e219 Inhibitors of the Renin-Angiotensin-Aldosterone System...e220 Other Anti-Ischemic Therapies...e221 Intra-Aortic Balloon Pump Counterpulsation...e221 Analgesic Therapy...e221 Recommendations for Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite (UPDATED)...e221 Antiplatelet Therapy: Recommendations (UPDATED)...e221 Anticoagulant Therapy: Recommendations...e223 Additional Management Considerations for Antiplatelet and Anticoagulant Therapy: Recommendations (UPDATED)...e223 Antiplatelet/Anticoagulant Therapy in Patients for Whom Diagnosis of UA/NSTEMI Is Likely or Definite (NEW SECTION)...e224 Newer P2Y12 Receptor Inhibitors...e224 Choice of P2Y12 Receptor Inhibitors for PCI in UA/NSTEMI...e227 Timing of Discontinuation of P2Y12 Receptor Inhibitor Therapy for Surgical Procedures...e227 Interindividual Variability in Responsiveness to Clopidogrel...e228 Optimal Loading and Maintenance Dosages of Clopidogrel...e228 Proton Pump Inhibitors and Dual Antiplatelet Therapy for ACS...e229 Glycoprotein IIb/IIIa Receptor Antagonists (Updated to Incorporate Newer Trials and Evidence)...e230 Older Antiplatelet Agents and Trials (Aspirin, Ticlopidine, Clopidogrel)...e231 Aspirin...e231 Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents...e233 Anticoagulant Agents and Trials...e236 Unfractionated Heparin...e237 Low-Molecular-Weight Heparin...e238 LMWH Versus UFH...e238 Extended Therapy with LMWHs...e241 Direct Thrombin Inhibitors...e241 Factor Xa Inhibitors...e244 Long-Term Anticoagulation...e245 Platelet GP IIb/IIIa Receptor Antagonists...e246 Fibrinolysis...e251 Initial Conservative Versus Initial Invasive Strategies (UPDATED)...e251 General Principles...e252 Rationale for the Initial Conservative Strategy...e252 Rationale for the Invasive Strategy...e253 Timing of Invasive Therapy (NEW SECTION)...e253 Immediate Angiography...e254 Deferred Angiography...e254 Comparison of Early Invasive and Initial Conservative Strategies...e254 Subgroups...e257 Care Objectives...e258 Risk Stratification Before Discharge...e260 Care Objectives...e260 Noninvasive Test Selection...e262 Selection for Coronary Angiography...e263 Patient Counseling...e263 Coronary Revascularization...e263 Recommendations for Revascularization With PCI and CABG in Patients With UA/NSTEMI (UPDATED)...e263 Late Hospital Care, Hospital Discharge, and Post-Hospital Discharge Care...e263 Medical Regimen and Use of Medications...e263 Long-Term Medical Therapy and Secondary Prevention...e265 Convalescent and Long-Term Antiplatelet Therapy (UPDATED)...e266 Beta Blockers...e266 Inhibition of the Renin-Angiotensin-Aldosterone System...e267 Nitroglycerin...e267 Calcium Channel Blockers...e267 Warfarin Therapy (UPDATED)...e267 Lipid Management...e268 Blood Pressure Control...e270 Diabetes Mellitus...e270 Smoking Cessation...e270 Weight Management...e271 Physical Activity...e271 Patient Education...e272 Influenza...e272 Depression...e272 Nonsteroidal Anti-Inflammatory Drugs...e272 Hormone Therapy...e272 Antioxidant Vitamins and Folic Acid...e273 Postdischarge Follow-Up...e273 Cardiac Rehabilitation...e274 Return to Work and Disability...e275 Other Activities...e276 Patient Records and Other Information Systems...e277 Special Groups...e277 Women...e277 Profile of UA/NSTEMI in Women...e278 Management...e278 Pharmacological Therapy...e278 Coronary Artery Revascularization...e278 Initial Invasive Versus Initial Conservative Strategy...e279 Stress Testing...e281 Conclusions...e281 Diabetes Mellitus (UPDATED)...e281 Profile and Initial Management of Diabetic and Hyperglycemic Patients With UA/NSTEMI...e281 Intensive Glucose Control (NEW SECTION)...e282 Coronary Revascularization...e283 Conclusions...e284 Post-CABG Patients...e284 Pathological Findings...e285 Clinical Findings and Approach...e285 Conclusions...e285 Older Adults...e285 Pharmacological Management...e286 Functional Studies...e286 Percutaneous Coronary Intervention in Older Patients...e287 Contemporary Revascularization Strategies in Older Patients...e287 Conclusions...e287 Chronic Kidney Disease (UPDATED) ...e288 Angiography in Patients With CKD (NEW SECTION)...e288 Cocaine and Methamphetamine Users...e290 Coronary Artery Spasm With Cocaine Use...e290 Treatment...e291 Methamphetamine Use and UA/NSTEMI...e292 Variant (Prinzmetal's) Angina...e292 Clinical Picture...e292 Pathogenesis...e292 Diagnosis...e293 Treatment...e293 Prognosis...e293 Cardiovascular "Syndrome X"...e294 Definition and Clinical Picture...e294 Treatment...e295 Takotsubo Cardiomyopathy...e295 Conclusions and Future Directions...e295 Recommendations for Quality of Care and Outcomes for UA/NSTEMI (NEW SECTION)...e297 Quality Care and Outcomes (NEW SECTION)...e297 References...e297 Appendix 1.
The relationship between liver interleukin-6 (IL-6) resistance following high-fat diet (HFD)-induced obesity and glucose intolerance is unclear. The purpose of this study was to assess the temporal ...development of hepatic IL-6 resistance and the role of endoplasmic reticulum (ER) stress in this process. We hypothesized that HFD would rapidly induce hepatic IL-6 resistance through a mechanism involving ER stress. Male C57BL/6N mice consumed chow or a HFD (60%) derived from lard (saturated) or olive oil (monounsaturated) for 4 days or 7 weeks before being injected intraperitoneally with IL-6 (6 ng·kg−1). Glucose, insulin, and pyruvate tolerance tests were used as proxies for systemic glucose metabolism and hepatic glucose production, respectively. Primary mouse hepatocytes were incubated with palmitate (saturated) and oleate (unsaturated) overnight, then treated with 20 ng/ml IL-6. ER stress was induced via tunicamycin or prevented by sodium phenylbutyrate (PBA). Seven weeks of a saturated, but not monounsaturated, HFD reduced hepatic IL-6 signaling in conjunction with hepatic ER stress. Palmitate directly impaired IL-6 signaling in hepatocytes along with inducing ER stress. Pharmacologically induced ER stress caused hepatic IL-6 resistance, whereas PBA reversed HFD-induced IL-6 resistance. Chronic HFD-induced obesity is associated with hepatic IL-6 resistance due to saturated FA-induced ER stress.
Among more than 3000 hospitalized patients with Covid-19, recipients of high-titer convalescent plasma had a lower mortality at 30 days than recipients of low-titer plasma. The effect of high-titer ...plasma was greatest in the subgroup of patients who were not receiving mechanical ventilation.
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