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Key Points Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD. Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials. Inclisiran showed sustained and effective LDL cholesterol–lowering in patients across various levels of eGFR values, without new safety findings. Background Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11). Methods Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 . Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated. Results Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m 2 . The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m 2 were −49.9% (−53.2 to −46.6), −51.2% (−54.4 to −48.0), −54.7% (−62.5 to −47.0), and −44.7% (−57.6 to −31.8), respectively ( P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were −48.4% (−50.8 to −46.1), −51.8% (−54.2 to −49.4), −55.6% (−61.0 to −50.2), and −50.4% (−59.3 to −41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings. Conclusions Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m 2 , without new safety findings. Clinical Trial registry name and registration number: ClinicalTrials.gov, ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800).

Abstract Background Obstructive sleep apnea (OSA) is a risk factor for hypertension and some evidence suggests this risk may not be mitigated with positive airway pressure. Low-intensity statin therapy can modestly reduce blood pressure (BP). In this exploratory analysis, we examined if six months of high-intensity statin therapy could lower resting or ambulatory BP in patients with OSA. Methods 39 patients with OSA (13F, age = 49 ± 9yrs, body mass index = 32.9 ± 4.2kg/m2, apnea-hypopnea index = 22.2 ± 12.4 events/hour) were randomized to high-intensity atorvastatin or placebo. BP was assessed using seated, “office” measurements and in 20-minute intervals over 24 consecutive hours at three timepoints (baseline, three- and six-months post-randomization). Participants maintained a diary denoting sleep and wake times for analysis. Changes (Δ) in BP from baseline were assessed and adjusted for adherence to participants’ intervention (atorvastatin or placebo) as well as to their treatment for OSA (yes or no). Results There were no between-group differences in baseline BP variables (P = .09-.96). At three months, the changes in resting (P = .74-.87), 24 hour mean (P = .54-.96), daytime (P = .70-.96), nor nighttime (P = .74-.96) BP did not differ between groups. Similarly, the changes in resting (P = .23-.92), 24 hour mean (P = .51-.82), daytime (P = .17-.78), and nighttime (P = .51-1.00) BP did not differ between groups following six months of their respective intervention. Conclusions Our data suggest that high-intensity atorvastatin does not lower resting or ambulatory BP in patients with OSA relative to a placebo. Thus, it does not appear that atorvastatin is a viable adjunct intervention for BP reduction in patients with OSA. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03308578.

Abstract Aims To evaluate whether the effect of inclisiran to lower LDL-C varied by background lipid-lowering therapy (LLT). Methods and results In ORION-10 and ORION-11 Phase 3 trials, patients (N = 3178) with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents were randomized 1:1 to receive inclisiran or placebo on Day 1, Day 90, and 6-monthly thereafter. In this pooled post hoc analysis, patients were stratified by baseline combination therapy [statin plus ezetimibe (n = 214; 6.7%)], monotherapy [statin (n = 2711; 85.3%) or ezetimibe (n = 54; 1.7%)], or neither LLT [none (n = 199; 6.3%)] into therapy groups with/without other LLT. Stratification by baseline statin intensity was also performed (N = 3155). Relative and absolute changes in LDL-C were assessed. Mean (±SD) baseline LDL-C was 2.7 mmol/L (±1.0), 2.6 mmol/L (±0.9), 3.7 mmol/L (±1.7), and 4.1 mmol/L (±1.5) among patients receiving combination, statin, ezetimibe, or neither LLT, respectively. In these categories, mean (95% confidence interval) time-adjusted, placebo-corrected percentage change in LDL-C after Day 90 to Day 540 with inclisiran were −57.0% (−63.8, −50.1), −51.5.% (−53.4, −49.7), −50.5.% (−59.6, −41.5), and −43.1% (−48.7, −37.6); corresponding absolute changes were −1.5 mmol/L (−1.7, −1.3), −1.3 mmol/L (−1.4, −1.3), −1.7 mmol/L (−2.0, −1.4), and −1.7 mmol/L (−1.9, −1.5). Conclusion Sustained and effective LDL-C lowering with inclisiran was observed irrespective of background LLT treatment. Inclisiran was overall well tolerated with all background LLT treatments, consistent with its established safety profile.

Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10–20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

Abstract Aims To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. Materials and Methods Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3‐month doses up to 18 months, with background oral lipid‐lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m 2 ). Co‐primary endpoints were percentage and time‐adjusted percentage change in low‐density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. Results Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo‐corrected) with inclisiran from baseline to Day 510 ranged from −47.6% to −51.9% and from −48.8% to −54.4% across glycaemic/BMI strata, respectively. Similarly, time‐adjusted percentage changes after Day 90 and up to Day 540 ranged from −46.8% to −52.0% and from −48.6% to −53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment‐emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%–7.7%) versus placebo (0.2%–2.1%). Conclusion Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild‐to‐moderate TEAEs at the injection site.

Abstract Aims Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials. Methods and results Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: &lt; 1.8 mmol/L (&lt; 70 mg/dL); ASCVD risk equivalent: &lt; 2.6 mmol/L (&lt; 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was −49.4% (95% CI: −50.4, −48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified. Conclusion In the largest and longest follow-up to date with &gt;12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile. Trial Registration number ClinicalTrials.gov identifier: NCT03814187

Background: Patients suffering post operative myocardial infarction (PMI) have higher mortality and morbidity rates than observed with non-PMI subsets. Little is known about the true incidence of PMI and how PMI differs from non-PMI with regard to clinical presentation, management and outcome. Methods: We examined the incidence and outcomes of patients with PMI in 1212 subjects (≥65 years) undergoing hip fracture surgery from 1988 – 2002 using a population-based retrospective cohort study from the Rochester Epidemiology Project in Olmstead County, Minnesota. PMI was defined on the basis of cardiac biomarker and/or electrocardiographic evidence of definitive MI within 7 days post operatively. Results: PMI occurred in 170 (14.0%) patients yet only 36 (21.2 %) patients had one or more clinical symptoms suggesting coronary ischemia. One or more classic symptoms of myocardial infarction were present in 26 (15.3%) including shortness of breath (SOB) in 18 (10.6%), chest/arm pain in 11 (6.5%), nausea/vomiting in 8 (4.7%) and diaphoresis in 1 (0.6%). Delirium was present in 15 (8.8%) patients. Median hospital length of stay was longer (10.0 vs. 8 days, p<0.01) and the in-hospital mortality rate was significantly higher (14.1% vs. 1.6%, p<0.001) among patients who had PMI within 7 days. Conclusion: The clinical presentation of PMI differs from non-PMI in the elderly undergoing hip fracture surgery. Most patients were asymptomatic or had atypical clinical presentations. We observed a significantly higher rate of hospital mortality among those experiencing a PMI. Further studies are necessary to better understand the presentation, optimal management and prevention of PMI. Table 1. Study Population Table 2. Clinical Presentation and Outcomes in Patients with and without Post Operative MI This research has received full or partial funding support from the American Heart Association, National Center.