Home NIV treatment quality in patients with chronic respiratory failure having participated to the French nationwide telemonitoring experimental program (The TELVENT study).

BACKGROUND: The ETAPES program is a national telemedicine experiment conducted in France between 2018 and 2023 to investigate whether home non-invasive ventilation (NIV) telemonitoring improves healthcare pathways in patients with chronic respiratory failure (CRF) and impacts healthcare organization. The program provides a combination of therapeutic education and NIV telemonitoring with data processed by an algorithm generating alerts. The TELVENT study objective was to analyze the evolution of ventilation quality in patients included in the ETAPES program. METHODS: Multicentric cohort study on patients undergoing long-term NIV included in the ETAPES program between September 2018 and December 2020 and who did not refuse the use of their data for this research. Data were obtained from homecare provider databases. The primary endpoint was to attain successful NIV treatment, which was determined by a combination of daily NIV usage for > 4 h per day, low leaks, and a low apnea-hypopnea index (AHI) identified by the NIV device. Respiratory disability was assessed using the DIRECT questionnaire. RESULTS: 329 patients were included in the study of which 145 had COPD and 83 had started NIV and ETAPES within one-month delay. Approximately 25% of patients did not achieve the criteria for successful NIV at ETAPES entry. The proportion of patients with successful NIV treatment increased to 86.8% at six months (p = 0.003, Cochran-Armitage trend test) regardless of NIV history and continued to increase at 12 months in newly equipped NIV patients (93.8%, at month 12, p = 0.0026 for trend test). Over time, a significant increase in NIV use and compliance was observed, while AHI significantly decreased in the overall population. No significant decrease was observed for non-intentional leaks. Approximately 4.9 alerts were generated per patient per 6 months. Their number and type (low NIV use, high AHI or leaks) differed among patients based on their NIV history. Respiratory disability score decreased over time compared with baseline. CONCLUSION: The TELVENT study highlights the importance of remote NIV monitoring to rapidly identify patients with unsuccessful ventilation. The combination of remote monitoring and therapeutic education may improve the quality of home NIV, especially in the first months of treatment.

Lung cancer trends and tumor characteristic changes over 20 years (2000-2020): Results of three French consecutive nationwide prospective cohorts' studies.

Background: Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort. Methods: KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010. Findings: In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 (p<0·0001). The proportion of non-smokers was higher in 2020 (12·6%, 1129/8983) than in previous cohorts (10·9% (762/7008) in 2010; 7·2% (402/5586) in 2000, p<0·0001). In 2020, at diagnosis, 57·6% (4405/7648) of patients had a metastatic/disseminated stage non-small-cell lung cancer (NSCLC) (58·3% (3522/6046) in 2010; 42·6% (1879/4411) in 2000, p<0·0001). Compared with 2000 and 2010 data, early survival improved slightly. In 2020, 3-month mortality of NSCLC varied from 3·0% [2·2 - 3·8] for localized to 9·6% [8·1 - 11·0] for locally advanced to 29·2% [27·8 - 30·6] for metastatic and was 24·8% [22·3 - 27·3] for SCLC. Interpretation: To our knowledge KBP cohorts have been the largest, prospective, real-world cohort studies involving LC patients conducted in worldwide. The trend found in our study shows an increase in LC in women and still a large proportion of patients diagnosed at metastatic or disseminated stage. Funding: The study was promoted by the French College of General Hospital Pulmonologists with financial support of industrials laboratories.

Safety and efficacy of alirocumab in a real-life setting: the ODYSSEY APPRISE study.

AIMS: To obtain safety and efficacy data of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting in high cardiovascular (CV) risk patients with heterozygous familial hypercholesterolaemia (HeFH) or very-high low-density lipoprotein cholesterol (LDL-C) levels despite maximally tolerated dose of statin ± other lipid-lowering therapies (MTD ± LLTs). ODYSSEY APPRISE was a prospective, single-arm, Phase 3b open-label (≥12 weeks to ≤ 30 months) European/Canadian study with alirocumab. METHODS AND RESULTS: Patients received alirocumab 75 or 150 mg every 2 weeks, with dose adjustment based on physician's judgment. In total, 994 patients were enrolled and treated. The mean [standard deviation (SD)] duration of alirocumab exposure was 72.4 (42.5) weeks. Patients with HeFH were younger [mean (SD) age of 53.8 (11.6) vs. 61.6 (10.1) years], more likely to be female (41.7% vs. 29.1%) and had higher baseline LDL-C compared with non-familial hypercholesterolaemia (non-FH) patients [mean (SD) of 5.1 (1.7) vs. 4.1 (1.1) mmol/L]. The overall incidence of treatment-emergent adverse events (TEAEs) was 71.6%; common TEAEs included nasopharyngitis (7.8%), myalgia (7.1%), and headache (6.2%). At Week 12, mean (SD) LDL-C was reduced by 54.8 (20.1)% from baseline [2.6 (1.2) mmol/L], maintained for the trial duration. LDL-C was reduced below 1.8 mmol/L and/or by ≥50% reduction from baseline in 69.1% of patients overall, and for 64.7 and 77.4% of the HeFH and non-FH subgroups, respectively. CONCLUSION: In a real-life setting in patients with hypercholesterolaemia and high CV risk, alirocumab was generally well tolerated and resulted in clinically significant LDL-C reductions.

LDL-C calculated by Friedewald, Martin-Hopkins, or NIH equation 2 versus beta-quantification: pooled alirocumab trials.

Accurate assessment of LDL-C levels is important, as they are often used for treatment recommendations. For many years, plasma LDL-C levels were calculated using the Friedewald equation, but there are limitations to this method compared with direct measurement via beta-quantification (BQ). Here, we assessed differences between the Friedewald, Martin-Hopkins, and NIH equation 2 methods of calculating LDL-C and the "gold standard" BQ method using pooled phase 3 data with alirocumab. All randomized patients were included irrespective of the treatment arm (n = 6,122). We compared pairs of LDL-C values (n = 17,077) determined by each equation and BQ. We found that BQ-derived LDL-C values ranged from 1 to 397 mg/dl (mean 90.68 mg/dl). There were strong correlations between Friedewald-calculated, Martin-Hopkins-calculated, and NIH equation 2-calculated LDL-C with BQ-determined LDL-C values (Pearson's correlation coefficient = 0.985, 0.981, and 0.985, respectively). Importantly, for BQ-derived LDL-C values ≥70 mg/dl, only 3.2%, 1.4%, and 1.8% of Friedewald-calculated, Martin-Hopkins-calculated, and NIH equation 2-calculated values were <70 mg/dl, respectively. When triglyceride (TG) levels were <150 mg/dl, differences between calculated and BQ-derived LDL-C values were minimal, regardless of the LDL-C level (<40, <55, or <70 mg/dl). However, when TG levels were >150 mg/dl, NIH equation 2 provided greater accuracy than Friedewald or Martin-Hopkins. When TGs were >250 mg/dl, inaccuracies were seen with all three methods, although NIH equation 2 remained the most accurate. In conclusion, LDL-C calculated by any of the three methods can guide treatment decisions for most patients, including those treated with proprotein convertase subtilisin/kexin type 9 inhibitors.

Long Term Outcomes of Liver Transplantation For Patients With Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). Data on the long-term outcomes of living-related LT for AIH are limited and inconsistent. The present study aimed to assess the long-term outcomes of deceased donor LT (DDLT) and living donor LT (LDLT) for AIH. METHODS: All patients who received transplants for AIH-related cirrhosis from 2001 to 2018 were included in this study. RESULTS: Seventy-four patients (31 male, 43 female) received LT. The average follow-up was 7.9 ± 6.9 years (median = 7.2 years), average age was 34.3 ± 13.8 years, and average Model for End-Stage Liver Disease (MELD) score was 23.6 ± 8.5. Thirty-six (49.3%) patients received a graft from a living donor, and 83% of patients were maintained on steroids. The 1-, 3-, 5-, and 10-year survival rates of patients were 91%, 89%, 87%, and 82% and of grafts were 89%, 88%, 86%, and 76%, respectively. In univariate analysis, MELD score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17; P = .028), donor age (OR per 5 years, 1.45; 95% CI, 1.07-2.02; P = .021), donor type (OR LDLT vs DDLT, 0.19; 95% CI, 0.04-0.67; P = .017), and renal function (OR glomerular filtration rate <60 vs ≥60 mL/min/m2, 7.41; 95% CI, 1.88-31.25; P = .004) were significant predictors of graft survival; however, none of the factors remained significant in multivariate analysis. CONCLUSION: We have shown the highest reported long-term survival rates in LT for AIH, including a large number of patients who underwent LDLT. Standardized management and immunosuppressive therapy, including the maintenance of a low-dose steroid protocol, may have contributed to this outcome.

Regulatory T cell/Th17 balance in the pathogenesis of paediatric Behçet disease.

OBJECTIVES: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance. METHODS: T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated. RESULTS: Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells. CONCLUSION: There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response.

Regional Variations in Alirocumab Dosing Patterns in Patients with Heterozygous Familial Hypercholesterolemia During an Open-Label Extension Study.

PURPOSE: During the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician-patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW). METHODS: Patients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible. RESULTS: Mean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns. CONCLUSIONS: In this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.

Triglyceride concentrations and non-high-density lipoprotein cholesterol goal attainment in the ODYSSEY phase 3 trials with alirocumab.

AIMS: Guidelines recommend targeting non-high-density lipoprotein cholesterol to reduce cardiovascular risk. We assessed the impact of baseline triglycerides on non-high-density lipoprotein cholesterol goal attainment in 10 phase 3 trials with alirocumab versus control (n = 4983). METHODS: Trials were grouped into four pools based on alirocumab dose (75-150 mg every 2 weeks), control (placebo/ezetimibe) and statin use. Baseline triglyceride quintiles were built within each pool. Non-high-density lipoprotein cholesterol goal attainment (very high risk: <100 mg/dl; moderate/high risk: <130 mg/dl), low-density lipoprotein cholesterol goal attainment (very high risk: <70 mg/dl; moderate/high risk: <100 mg/dl) and changes from baseline in lipid parameters were assessed at Week 24 among baseline triglyceride quintiles. RESULTS: Higher baseline triglycerides were associated with a worse cardiovascular risk profile. Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol increased with higher triglycerides, but the magnitude in non-high-density lipoprotein cholesterol was three- to four-fold higher compared with the increase in low-density lipoprotein cholesterol. Non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol percentage reductions from baseline with alirocumab were similar regardless of baseline triglycerides. A greater proportion of alirocumab-treated patients attained non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol goals compared with placebo or ezetimibe. Unlike low-density lipoprotein cholesterol goal attainment, non-high-density lipoprotein cholesterol goal attainment significantly declined with increasing baseline triglycerides (p < 0.05 for trend tests). A single standard deviation increase in baseline log(triglycerides) was significantly associated with lower odds ratios of attaining non-high-density lipoprotein cholesterol goals in the different pools and treatment (alirocumab/placebo/ezetimibe) groups, unlike low-density lipoprotein cholesterol goal attainment. CONCLUSION: Individuals with increased triglycerides have higher non-high-density lipoprotein cholesterol levels and lower rates of non-high-density lipoprotein cholesterol goal attainment (unlike low-density lipoprotein cholesterol goal attainment). Alirocumab improves non-high-density lipoprotein cholesterol goal attainment in this population. These results highlight the impact of triglycerides on non-high-density lipoprotein cholesterol and the need for novel therapies targeting triglyceride-related pathways.

Effect of alirocumab on individuals with type 2 diabetes, high triglycerides, and low high-density lipoprotein cholesterol.

BACKGROUND: Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM. METHODS: The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). RESULTS: Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed. CONCLUSIONS: Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.

Ocular symptoms improvement from intranasal triamcinolone compared with placebo and intranasal fluticasone propionate: A meta-analysis.

BACKGROUND: Allergic rhinitis is a prevalent disease, which can be classed as seasonal (SAR) or perennial. In addition to nasal symptoms, up to 75% of sufferers experience itching, redness, and tearing of the eyes. Intranasal corticosteroids are effective in controlling the allergic nasal symptoms, and increasing evidence suggests that they also can relieve some of the allergic ocular symptoms. OBJECTIVE: To evaluate the magnitude of efficacy of triamcinolone acetonide (TAA) compared with placebo or fluticasone propionate (FP) on ocular symptom improvement in patients with SAR. METHODS: A meta-analysis of summary data from 8 randomized, double- or single-blind trials, assessing mean change in total or individual (tearing, redness, and itching) eye symptoms was conducted. Trials that administered a daily dose of 220 µg TAA vs placebo or 200 µg FP over at least 2 weeks' duration, in patients aged 12 years or older with SAR, were analyzed. RESULTS: Total eye symptom reduction after 2 weeks was greater with TAA than placebo, with a mean treatment difference of -0.32 (95% CI, -0.444 to -0.203). In addition, significant reductions in tearing, but not itching or redness, were observed after TAA treatment compared with placebo. No significant treatment difference was seen between TAA and FP in total ocular symptoms at any of the time points measured (weeks 1, 2, 3, and overall). All treatments exhibited similar safety profiles and were deemed well tolerated. CONCLUSION: The meta-analysis demonstrated the positive clinical improvements TAA has on total ocular allergy symptoms, especially tearing, in addition to its recognized nasal symptom efficacy in SAR.

Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies.

BACKGROUND: Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS: In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS: This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS: Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery.

BACKGROUND: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. OBJECTIVES: This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). METHODS: Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003). RESULTS: In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). CONCLUSIONS: Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Treatment effect of alirocumab according to age group, smoking status, and hypertension: Pooled analysis from 10 randomized ODYSSEY studies.

BACKGROUND: Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. OBJECTIVE: We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. METHODS: Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24-104 weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non-familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age (<65, ≥65 to <75, ≥75 years) and baseline hypertension or smoking status. RESULTS: Alirocumab reduced LDL-C by 23.7% (75/150 mg vs ezetimibe + statin) to 65.4% (150 mg vs placebo + statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups. CONCLUSIONS: In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups.

Associations between lower levels of low-density lipoprotein cholesterol and cardiovascular events in very high-risk patients: Pooled analysis of nine ODYSSEY trials of alirocumab versus control.

BACKGROUND AND AIMS: Guidelines recommend high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). Subgroups with comorbidities that increase cardiovascular risk, such as diabetes mellitus (DM), chronic kidney disease (CKD) or polyvascular disease (PoVD), may derive greater absolute benefit from addition of non-statin therapies. We assessed the relationship between lower low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) risk reduction during alirocumab phase III ODYSSEY trials among these subgroups. METHODS: Patient data were pooled from nine trials comparing alirocumab with control (placebo/ezetimibe), predominantly on background maximally tolerated statin. Patients with baseline ASCVD were stratified into subgroups with DM, CKD or PoVD, or without comorbidities, and between-group relative and absolute benefits were compared. RESULTS: Among 3505 patients with ASCVD, 1573 had no comorbidities, 981 had DM, 660 had CKD and 943 had PoVD, with overlap between comorbidities; mean baseline LDL-C levels were 119 (ASCVD overall), 123, 117, 114 and 113 mg/dL, respectively. Overall, each 39 mg/dL lower on-study LDL-C was associated with a 25% lower MACE risk, hazard ratio 0.75 (95% confidence interval, 0.62-0.90, p = 0.0023), with a similar lower risk observed in each very high-risk subgroup (DM, CKD or PoVD; 30-35%) but not in the subgroup without these comorbidities (9%). Absolute benefits were greater for very high-risk subgroups; lowering LDL-C from 120 to 40 mg/dL would result in 2.76-4.35 fewer MACE/100 patient-years versus 0.3 for no comorbidities. CONCLUSIONS: Among patients with ASCVD and mean baseline LDL-C >100 mg/dL, patients with DM, CKD or PoVD appeared to derive greater absolute cardiovascular benefits from further LDL-C reduction than those without.

PCSK9 inhibition in patients with and without prior myocardial infarction or ischemic stroke: A pooled analysis of nine randomized-controlled studies of alirocumab.

BACKGROUND: Patients with prior cardiovascular events are at very high risk of recurrent events and may benefit from low-density lipoprotein cholesterol (LDL-C) lowering beyond that achieved with maximally tolerated statins. OBJECTIVE: To assess potential differences between the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab, in patients with vs without prior myocardial infarction (MI)/ischemic stroke. METHODS: Data (n = 4880) were pooled from nine ODYSSEY phase 3 trials of alirocumab 75/150 mg or 150 mg every 2 weeks, mostly on background statins ± other lipid-lowering therapies. Analyses were performed according to statin status, alirocumab dose, and control (placebo or ezetimibe). RESULTS: Baseline LDL-C, non-high-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein B levels were lower and lipoprotein(a) higher in patients with than without prior MI/ischemic stroke. LDL-C levels were reduced from baseline to week 24 in patients with (51.1%-62.9%) and without (43.6%-58.3%) prior MI/ischemic stroke, with no significant interaction between prior MI/ischemic stroke status and LDL-C-lowering efficacy of alirocumab vs controls. Alirocumab significantly reduced other lipid/lipoproteins (including lipoprotein[a]) similarly in patients with/without MI/ischemic stroke. Week 24 LDL-C goal attainment rates for subgroups with/without prior MI/ischemic stroke on background statins were 74.1%-84.8% and 63.7%-74.7%, respectively. The safety profile of alirocumab was generally similar regardless of prior MI/ischemic stroke status. CONCLUSIONS: Alirocumab significantly reduced LDL-C and other atherogenic lipids/lipoproteins in patients with prior MI/ischemic stroke, and the majority of this very high cardiovascular risk population achieved LDL-C goals; efficacy and safety results were similar in patients without prior MI/ischemic stroke.

Lower On-Treatment Low-Density Lipoprotein Cholesterol and Major Adverse Cardiovascular Events in Women and Men: Pooled Analysis of 10 ODYSSEY Phase 3 Alirocumab Trials.

Background In statin trials, men and women derived similar relative risk reductions in cardiovascular events per 39 mg/ dL low-density lipoprotein cholesterol ( LDL -C) reduction. We explored whether lower LDL -C levels and greater LDL -C percentage reductions than those achieved with statins are associated with reduced major adverse cardiovascular event ( MACE ) rates in women as well as men. Methods and Results Data pooled from 10 phase 3 ODYSSEY randomized trials (n=4983) comparing alirocumab with control (placebo/ezetimibe) were assessed for association between 39 mg/dL lower on-treatment LDL -C and percentage LDL -C change from baseline, and MACE risk by sex, using multivariable Cox regression. Mean baseline LDL -C was 135 mg/dL (women) and 121 mg/dL (men). Average on-treatment LDL -C levels with alirocumab, ezetimibe, and placebo were 71, 114, and 134 mg/dL, respectively, in women (n=1882) and 52, 93, and 122 mg/dL, respectively, in men (n=3090). Overall, 36.5% and 58.7% of women and men, respectively, achieved on-treatment LDL -C <50 mg/dL. Each 39 mg/dL lower LDL -C was associated with a 33% and 22% lower risk of MACE in women ( P=0.0209) and men ( P=0.0307), respectively, with no significant between-sex difference ( P for heterogeneity=0.4597). Results were similar when analyzed per 50% LDL -C reduction, 24% ( P=0.1094) and 29% ( P=0.0125) lower MACE risk in women and men, respectively ( P for heterogeneity=0.7499). Alirocumab was generally well tolerated in both sexes. Conclusions The present analysis reinforces the notion that both sexes derive a similar cardiovascular benefit from LDL -C lowering. Although women had slightly higher on-treatment LDL -C than men, both sexes showed a similar lower MACE risk with lower LDL -C.

Efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus with or without mixed dyslipidaemia: Analysis of the ODYSSEY LONG TERM trial.

BACKGROUND AND AIMS: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, significantly reduces low-density lipoprotein cholesterol (LDL-C). We evaluated the efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus (T2DM) with versus without mixed dyslipidaemia (MDL, defined as baseline LDL-C ≥70 mg/dL [1.8 mmol/L] and triglycerides ≥150 mg/dL [1.7 mmol/L]). METHODS: Data from 812 individuals with T2DM, from the placebo-controlled, 78-week, Phase 3 ODYSSEY LONG TERM trial of alirocumab 150 mg every 2 weeks (Q2W), on a background of maximally tolerated statins ±â€¯other lipid-lowering therapies, were pooled according to MDL status. Efficacy endpoints included percentage change from baseline to Week 24 in calculated LDL-C and other lipids/lipoproteins. RESULTS: In individuals with T2DM who received alirocumab 150 mg Q2W, mean LDL-C changes from baseline to Week 24 were -62.6% (vs. -6.0% with placebo) in those with MDL and -56.1% (vs. 5.6%) in those without MDL, with no significant between-group difference (p-interaction = 0.0842). Risk-based LDL-C goals (<70 [1.8 mmol/L] or <100 mg/dL [2.6 mmol/L]) were achieved by 69.1% and 72.4% of alirocumab-treated individuals with and without MDL, respectively. Mean reductions in non-high-density lipoprotein cholesterol (49.2% and 47.8%) and apolipoprotein B (50.2% and 49.1%) with alirocumab were also similar in those with and without MDL, respectively. Treatment-emergent adverse event rates were comparable between alirocumab-treated individuals with T2DM, with and without MDL. CONCLUSIONS: Reductions in LDL-C and other lipids with alirocumab, as well as safety and tolerability, were comparable between individuals with T2DM and with versus without MDL.

Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials.

AIMS: Individuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post-hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials. MATERIALS AND METHODS: Changes in low-density lipoprotein cholesterol (LDL-C) and other lipids from baseline to Week 24 were analysed (intention-to-treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no). RESULTS: At Week 24, LDL-C changes from baseline in pools with background statins were -61.5% with alirocumab 150 (vs -1.0% with placebo), -46.4% with alirocumab 75/150 (vs +6.3% with placebo) and -48.7% with alirocumab 75/150 (vs -20.6% with ezetimibe), and -54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL-C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non-high-density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78-104 weeks. Overall safety was similar between treatment groups, with a higher injection-site reaction frequency (mostly mild) with alirocumab. CONCLUSION: Alirocumab significantly reduced LDL-C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

Efficacy and Safety of Alirocumab in Individuals with Diabetes Mellitus: Pooled Analyses from Five Placebo-Controlled Phase 3 Studies.

INTRODUCTION: Diabetes mellitus (DM) carries an elevated risk for cardiovascular disease. Here, we assessed alirocumab efficacy and safety in people with/without DM from five placebo-controlled phase 3 studies. METHODS: Data from up to 78 weeks were analyzed in individuals on maximally tolerated background statin. In three studies, alirocumab 75 mg every 2 weeks (Q2W) was increased to 150 mg Q2W at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥ 70 mg/dL; two studies used alirocumab 150 mg Q2W throughout. The primary endpoint was percentage change in LDL-C from baseline to week 24. RESULTS: In the alirocumab 150 mg pool (n = 2416), baseline LDL-C levels were 117.4 mg/dL (DM) and 130.6 mg/dL (without DM), and in the 75/150 mg pool (n = 1043) 112.8 mg/dL (DM) and 133.0 mg/dL (without DM). In the 150 mg Q2W group, week 24 LDL-C reductions from baseline were observed in persons with DM (- 59.9%; placebo, - 1.4%) and without DM (- 60.6%; placebo, + 1.5%); 77.7% (DM) and 76.8% (without DM) of subjects achieved LDL-C < 70 mg/dL. In the alirocumab 75/150 mg group, 26% (DM) and 36% (without DM) of subjects received dose increase. In this group, week 24 LDL-C levels changed from baseline by - 43.8% (DM; placebo, + 0.3%) and - 49.7% (without DM; placebo, + 5.1%); LDL-C < 70 mg/dL was achieved by 68.3% and 65.8% of individuals, respectively. At week 24, alirocumab was also associated with improved levels of other lipids. Adverse event rates were generally comparable in all groups (79.8-82.0%). CONCLUSIONS: Regardless of DM status, alirocumab significantly reduced LDL-C levels; safety was generally similar. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc. Plain language summary available for this article.

Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease.

Individuals with chronic kidney disease are at increased risk of premature cardiovascular disease. Among them, many with elevated low-density lipoprotein cholesterol (LDL-C) are unable to achieve optimal LDL-C on statins and require additional lipid-lowering therapy. To study this, we compared the LDL-C-lowering efficacy and safety of alirocumab in individuals with hypercholesterolemia with impaired renal function, defined as eGFR 30-59 ml/min/1.73 m2, to those without impaired renal function eGFR ≥60 ml/min/1.73 m2. A total of 4629 hypercholesterolemic individuals without or with impaired renal function, pooled from eight phase 3 ODYSSEY trials (double-blind treatments of 24-104 weeks), were on alirocumab 150 mg or 75/150 mg every two weeks vs. placebo or ezetimibe. Overall, 10.1% had impaired renal function and over 99% were receiving statin treatment. Baseline LDL-C in alirocumab and control groups was comparable in subgroups analyzed. LDL-C reductions at week 24 ranged from 46.1 to 62.2% or 48.3 to 60.1% with alirocumab among individuals with or without impaired renal function, respectively. Similar reductions were observed for lipoprotein (a), non-high-density lipoprotein cholesterol, apolipoprotein B, and triglycerides. Safety data were similar in both treatment subgroups, regardless of the degree of CKD. Renal function did not change over time in response to alirocumab. This post hoc efficacy analysis is limited by evaluation of alirocumab treatment effects on renal and lipid parameters by serum biochemistry. Thus, alirocumab consistently lowered LDL-C regardless of impaired renal function, with safety comparable to control, among individuals with hypercholesterolemia who nearly all were on statin treatment.