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Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.
Ho Lee, Y, Gyu Song, G
Journal of clinical pharmacy and therapeutics. 2020;(4):674-681
Abstract
WHAT IS KNOWN AND OBJECTIVE Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.
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Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials.
Stein, EA, Giugliano, RP, Koren, MJ, Raal, FJ, Roth, EM, Weiss, R, Sullivan, D, Wasserman, SM, Somaratne, R, Kim, JB, et al
European heart journal. 2014;(33):2249-59
Abstract
AIMS: Prior trials with monoclonal antibodies to proprotein convertase subtilizin/kexin type 9 (PCSK9) reported robust low density lipoprotein cholesterol (LDL-C) reductions. However, the ability to detect potentially beneficial changes in other lipoproteins such as lipoprotein (a), triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A1, and adverse events (AEs) was limited by sample sizes of individual trials. We report a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9. METHODS AND RESULTS The trials randomized 1359 patients to various doses of subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or ezetimibe for 12 weeks; 1252 patients contributed to efficacy and 1314, to safety analyses. Mean percentage (95% CI) reductions in LDL-C vs. placebo ranged from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups (all P < 0.001). Statistically significant reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides and lipoprotein (a) [Lp(a)], and increases in HDL-C were also observed. Adverse events (AEs) and serious AEs with evolocumab were reported in 56.8 and 2.0% of patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and cerebrovascular events were reported in 0.3 and 0% in the placebo and 0.9 and 0.3% in the evolocumab arms, respectively. CONCLUSION In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favourable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.
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Effects of ezetimibe, simvastatin and ezetimibe/simvastatin on correlations between apolipoprotein B, LDL cholesterol and non-HDL cholesterol in patients with primary hypercholesterolemia.
Farnier, M, Guyton, JR, Jensen, E, Polis, AB, Johnson-Levonas, AO, Brudi, P
Atherosclerosis. 2013;(2):415-22
Abstract
BACKGROUND/SYNOPSIS Apolipoprotein (apo) B is highly predictive of coronary risk, especially in patients with high triglycerides (TG). This post hoc analysis evaluated the effects of lipid-lowering therapy on correlations between apoB and low-density lipoprotein cholesterol (apoB:LDL-C) and non-high-density lipoprotein cholesterol (apoB:non-HDL-C) in patients with TG< and ≥ 200 mg/dL. METHODS This analysis used data from 3 randomized clinical trials in patients with primary hypercholesterolemia receiving placebo, ezetimibe (EZE), simvastatin (SIMVA) or EZE/SIMVA for 12 weeks. Simple linear regression analyses predicted LDL-C and non-HDL-C levels corresponding to apoB values (80 mg/dL) at baseline and Week 12. RESULTS ApoB correlated with LDL-C (r ≥ 0.76) and non-HDL-C (r ≥ 0.86) at baseline. The correlations were strengthened with SIMVA and EZE/SIMVA at Week 12 (r ≥ 0.88 for LDL-C and r ≥ 0.94 for non-HDL-C). The predicted LDL-C and non-HDL-C values were lower following treatment with SIMVA or EZE/SIMVA than for placebo and EZE. For SIMVA and EZE/SIMVA, the predicted LDL-C and non-HDL-C values were closer to more aggressive LDL-C and non-HDL-C levels (i.e., 70 and 100 mg/dL, respectively). The apoB:LDL-C and apoB:non-HDL-C correlations were weaker and the predicted LDL-C values were generally lower in high TG patients than in low TG patients both at baseline and Week 12. In contrast, the predicted non-HDL-C values were generally higher in high versus low TG patients at baseline but less so at Week 12. CONCLUSION After treatment with EZE, SIMVA, or EZE/SIMVA, a given apoB value corresponds to lower LDL-C and non-HDL-C levels than those obtained from untreated patients.
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Effect of high-dose statin versus low-dose statin plus ezetimibe on endothelial function: a meta-analysis of randomized trials.
Ye, Y, Zhao, X, Zhai, G, Guo, L, Tian, Z, Zhang, S
Journal of cardiovascular pharmacology and therapeutics. 2012;(4):357-65
Abstract
BACKGROUND Combining low-dose statin and ezetimibe reduces the low-density lipoprotein cholesterol (LDL-C) similar to high-dose statin. However, whether there is a difference in the effect of these 2 lipid-lowering regimes on endothelial function is still controversial. METHODS We performed a systematic search of databases (MEDLINE [1950 to September 2011], EMBASE [1966 to September 2011]) and references of identified studies. Completely published randomized controlled trials comparing the effect of high-dose statin with low-dose stain plus ezetimibe on endothelial function (flow-mediated dilation [FMD] method) were included in this study. RESULTS Six trials with a total of 213 participants were included in the meta-analysis. The pooled weighted mean difference of FMD did not differ between the 2 lipid-lowering regimes (0.22%; 95% confidence interval [CI]: -0.85%-1.29%, P = .68). Furthermore, no significant reduction in LDL-C and C-reactive protein (CRP) occurred with high-dose statin versus low-dose statin plus ezetimibe (pooled weighted mean differences of LDL-C and CRP were -4.12 mg/dL, 95% CI: -9.54-1.12 mg/dL, P = .12, and -0.02 mg/L, 95% CI: -0.31-0.27 mg/L, P = .89, respectively). CONCLUSIONS Based on the currently available evidence, combining a low-dose statin with ezetimibe may provide similar beneficial effects on endothelial function as high-dose statin.
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Nonvitamin-K-antagonist oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack: a systematic review and meta-analysis of randomized controlled trials.
Ntaios, G, Papavasileiou, V, Diener, HC, Makaritsis, K, Michel, P
Stroke. 2012;(12):3298-304
Abstract
BACKGROUND AND PURPOSE To assess whether the combined analysis of all phase III trials of nonvitamin-K-antagonist (non-VKA) oral anticoagulants in patients with atrial fibrillation and previous stroke or transient ischemic attack shows a significant difference in efficacy or safety compared with warfarin. METHODS We searched PubMed until May 31, 2012, for randomized clinical trials using the following search items: atrial fibrillation, anticoagulation, warfarin, and previous stroke or transient ischemic attack. Studies had to be phase III trials in atrial fibrillation patients comparing warfarin with a non-VKA currently on the market or with the intention to be brought to the market in North America or Europe. Analysis was performed on intention-to-treat basis. A fixed-effects model was used as more appropriate than a random-effects model when combining a small number of studies. RESULTS Among 47 potentially eligible articles, 3 were included in the meta-analysis. In 14 527 patients, non-VKAs were associated with a significant reduction of stroke/systemic embolism (odds ratios, 0.85 [95% CI, 074-0.99]; relative risk reduction, 14%; absolute risk reduction, 0.7%; number needed to treat, 134 over 1.8-2.0 years) compared with warfarin. Non-VKAs were also associated with a significant reduction of major bleeding compared with warfarin (odds ratios, 0.86 [95% CI, 075-0.99]; relative risk reduction, 13%; absolute risk reduction, 0.8%; number needed to treat, 125), mainly driven by the significant reduction of hemorrhagic stroke (odds ratios, 0.44 [95% CI, 032-0.62]; relative risk reduction, 57.9%; absolute risk reduction, 0.7%; number needed to treat, 139). CONCLUSIONS In the context of the significant limitations of combining the results of disparate trials of different agents, non-VKAs seem to be associated with a significant reduction in rates of stroke or systemic embolism, hemorrhagic stroke, and major bleeding when compared with warfarin in patients with previous stroke or transient ischemic attack.
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Achievement of recommended lipid and lipoprotein levels with combined ezetimibe/statin therapy versus statin alone in patients with and without diabetes.
Guyton, JR, Betteridge, DJ, Farnier, M, Leiter, LA, Lin, J, Shah, A, Johnson-Levonas, AO, Brudi, P
Diabetes & vascular disease research. 2011;(2):160-72
Abstract
Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81-6.48 mmol/L) receiving ezetimibe/statin or statin for 4-24 weeks. Percentages of patients achieving various targets were calculated among diabetes (n = 6541) and non-diabetes (n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.