Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial.

INTRODUCTION: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Novartis Pharma.

Recent developments in the management of patients resuscitated from cardiac arrest.

Cardiac arrest is the leading cause of death in Europe and the United States. Many patients who are initially resuscitated die in the hospital, and hospital survivors often have substantial neurologic dysfunction. Most cardiac arrests are caused by coronary artery disease; patients with coronary artery disease likely benefit from early coronary angiography and intervention. After resuscitation, cardiac arrest patients remain critically ill and frequently suffer cardiogenic shock and multiorgan failure. Early cardiopulmonary stabilization is important to prevent worsening organ injury. To achieve best patient outcomes, comprehensive critical care management is needed, with primary goals of stabilizing hemodynamics and preventing progressive brain injury. Targeted temperature management is frequently recommended for comatose survivors of cardiac arrest to mitigate the neurologic injury that drives outcomes. Accurate neurologic assessment is central to managing care of cardiac arrest survivors and should combine physical examination with objective neurologic testing, with the caveat that delaying neurologic prognosis is essential to avoid premature withdrawal of supportive care. A combination of clinical findings and diagnostic results should be used to estimate the likelihood of functional recovery. This review focuses on recent advances in care and specific cardiac intensive care strategies that may improve morbidity and mortality for patients after cardiac arrest.

Reduced creatine kinase release with statin use at the time of myocardial infarction.

BACKGROUND: Statin pre-treatment has been shown to reduce myocardial infarct size in animal models. We evaluated peak creatine kinase levels in humans based on concomitant or very early statin initiation following myocardial infarction. METHODS: We identified 66 consecutive patients who received a statin within 24 h of admission to our coronary care unit for myocardial infarction. Each statin patient was matched with three patients who had not received statin therapy (n=198). Statin patients were subgrouped into those receiving statin therapy at the time of infarction (n=44) and those initiated on statin therapy within 24 h of infarction (n=22). Peak total creatine kinase concentrations were compared between groups. A linear regression model was developed to test for differences in peak creatine kinase after adjusting for differences between groups. RESULTS: Patients receiving statin therapy within 24 h of admission had significantly smaller median peak creatine kinase concentrations compared to those not receiving a statin (416 IU/l [258, 992] vs. 699 IU/l [339, 1728]; p=0.020). Subgroup analysis revealed that the lower peak creatine kinase concentrations within the statin group were a result of lower creatine kinase concentrations in those patients on a statin at the time of myocardial infarction (399 IU/l [255, 869] vs. 678 IU/l [276, 1870]; p<0.05). This difference retained statistical significance after adjustment for differences between groups. CONCLUSION: Statin therapy at the time of myocardial infarction is associated with lower peak creatine kinase concentrations. This suggests that statins may exhibit protective effects in the setting of myocardial ischemia and/or infarction in humans.

Added value of new acute coronary syndrome computer algorithm for interpretation of prehospital electrocardiograms.

A new computerized acute coronary syndrome (ACS) computer algorithm has been developed with the aim of improving the electrocardiographic detection of acute myocardial ischemia and infarction in the emergency department (ED). The purpose of this study was to determine the added value of the new ACS algorithm in assisting ED physicians to obtain a more accurate diagnosis in patients with ACS. The new algorithm combines a rule-based decision tree, which uses well-known clinical criteria and a data-centered neural network model for more robust pattern recognition. Input parameters of the neural network model consist of morphology features of derived Frank X, Y, Z waveforms and the patient's gender and age. The neural network model was trained with electrocardiograms obtained from documented acute myocardial infarction patients at the Mayo Clinic who were a part of a research ACS database, which includes electrocardiograms (ECGs) of more than 5,000 individuals at hospital admission (1st ECG in the ED). The test set portion of the study was conducted in 2 steps: 1) One emergency physician and 1 cardiologist classified 1,902 clinically correlated out-of-hospital ECGs without seeing the interpretation statement from the algorithm into 1 of the following categories: 1) acute myocardial infarction, acute ischemia, or nonischemic; 2) After 9 months, the same 2 physicians classified the same group of ECGs but with the interpretation statement of the algorithm printed on the tracing. The results demonstrated that with the assistance of the new algorithm, the emergency physician and cardiologist improved their sensitivity of interpreting acute myocardial infarction by 50% and 26%, respectively, without a loss of specificity. The new algorithm also improved the emergency physician's acute ischemia interpretation sensitivity by 53% and still maintained a reasonable specificity (91%). The new ACS algorithm provides added value for improving acute ischemia and infarction detection in the ED.