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A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia.
Ge, X, Zhu, T, Zeng, H, Yu, X, Li, J, Xie, S, Wan, J, Yang, H, Huang, K, Zhang, W
BioMed research international. 2021;:8032978
Abstract
OBJECTIVES The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). METHODS A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: "AMG 145", "evolocumab", "SAR236553/REGN727", "alirocumab", "RG7652", "LY3015014", "RN316/bococizumab", "PCSK9", and "familial hypercholesterolemia" up to November 2020. Study quality was assessed with the Cochrane Collaboration's tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. RESULTS A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD -49.14%, 95% CI: -55.81 to -42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. CONCLUSION PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.
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Effects of Evolocumab on Low-Density Lipoprotein Cholesterol, Non-High Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a) by Race and Ethnicity: A Meta-Analysis of Individual Participant Data From Double-Blind and Open-Label Extension Studies.
Daviglus, ML, Ferdinand, KC, López, JAG, Wu, Y, Monsalvo, ML, Rodriguez, CJ
Journal of the American Heart Association. 2021;(1):e016839
Abstract
Background Prevalence of cardiovascular disease risk factors and rates of atherosclerotic cardiovascular disease outcomes vary across racial/ethnic groups. This analysis examined the effects of evolocumab on LDL-C (low-density lipoprotein cholesterol) levels and LDL-C goals achievement by race/ethnicity. Methods and Results Data from 15 phase 2 and 3 studies of treatment with evolocumab versus placebo or ezetimibe were pooled (n=7669). Results were analyzed by participant clinical characteristics and by self-identified race/ethnicity. Key outcomes included percent change from baseline in LDL-C, achievement of LDL-C <70 mg/dL, and LDL-C reduction of ≥50% at 12 weeks and at 1 to 5 years. Across 12-week studies, mean percent change in LDL-C from baseline in evolocumab-treated participants was -52% to -59% for White and -46% to -67% for non-White participants, across clinical characteristics groups. LDL-C <70 mg/dL was achieved in 43% to 84% and 62% to 94% and LDL-C reduction of ≥50% in 63% to 78% and 58% to 86%, respectively. In 1- to 5-year studies, mean percent change in LDL-C was -46% to -52% for White and -49% to -55% for non-White participants. LDL-C <70 mg/dL was achieved in 53% to 84% and 66% to 77%, and LDL-C reduction of ≥50% in 53% to 67% and 58% to 68%, respectively. The treatment effect on mean percent change in LDL-C differed only in participants with type 2 diabetes mellitus, with a larger reduction in Asian participants. The qualitative interaction P values were nonsignificant, indicating consistent directionality of effect. Conclusions Similar reduction in LDL-C levels with evolocumab was observed across racial/ethnic groups in 12-week and 1- to 5-year studies. Among those with diabetes mellitus, Asian participants had greater LDL-C reduction.
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Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Zhou, T, Zhang, Z, Luo, F, Zhao, Y, Hou, X, Liu, T, Wang, K, Zhao, H, Huang, Y, Zhang, L
JAMA network open. 2020;(10):e2015748
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Abstract
IMPORTANCE Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is. OBJECTIVE To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019. STUDY SELECTION Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included. DATA EXTRACTION AND SYNTHESIS Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5. RESULTS A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97). CONCLUSIONS AND RELEVANCE The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
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Interventions for chronic palmoplantar pustulosis.
Obeid, G, Do, G, Kirby, L, Hughes, C, Sbidian, E, Le Cleach, L
The Cochrane database of systematic reviews. 2020;(1):CD011628
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Abstract
BACKGROUND Palmoplantar pustulosis is a chronic inflammatory disease in which sterile, relapsing pustules appear on the palms and soles, possibly in conjunction with other symptoms. The previous Cochrane Review on this topic was published in 2006, before biological treatments were extensively used. OBJECTIVES To assess the effects of interventions for chronic palmoplantar pustulosis to induce and maintain complete remission. SEARCH METHODS We searched the following databases up to March 2019: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of the included studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA We considered RCTs including people with palmoplantar pustulosis or chronic palmoplantar pustular psoriasis assessing topical therapy, systemic therapy, combinations of topical or systemic therapies, or non-pharmacological therapies compared with placebo, no intervention, or each other. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. Our outcomes included 'Proportion of participants cleared or almost cleared', 'Proportion of participants with adverse effects serious or severe enough to cause withdrawal', 'Proportion of participants with at least 50% improvement in disease severity', and 'Proportion of participants with adverse effects'. MAIN RESULTS We included 37 studies (1663 participants; mean age 50 years (range 34 to 63); 24% males). These studies reported condition severity differently. Around half of the included trials stated the setting (hospitals, community clinics, or both). More than half of the studies were at high risk of bias in at least one domain. Our included studies assessed mainly systemic treatments (retinoids, ciclosporin, biologics, etretinate + PUVA (combination of psoralens and long-wave ultraviolet radiation) therapy combined, and antibiotics), but also topical treatments (dermocorticoids, vitamin D) and phototherapy (PUVA, ultraviolet A1 (UVA1)). Other interventions were assessed by single studies. The most common comparator was placebo. All results presented in this abstract were assessed in the short term (mean treatment duration was 11 weeks (range 8 to 24 weeks)) and are based on participants with chronic palmoplantar pustulosis. All outcome time point measurements were taken from baseline and assessed at the end of treatment. Short-term and long-term outcomes were defined as measurement up to 24 weeks after randomisation and between 24 and 104 weeks after randomisation, respectively. One trial (188 participants) assessed the topical vitamin D derivative maxacalcitol versus placebo and found that maxacalcitol may be more effective than placebo in achieving clearance (risk ratio (RR) 7.83, 95% confidence interval (CI) 1.85 to 33.12; low-quality evidence), and the risk of adverse effects (such as mild local irritation, pruritus, and haematological or urinary test abnormalities) is probably similar in both groups (RR 0.87, 95% CI 0.64 to 1.19; moderate-quality evidence). Severity was not reported. Two trials (49 participants) assessed PUVA therapy versus placebo or no treatment, providing very low-quality evidence. Adverse effects were reported with oral PUVA (including nausea, ankle swelling, and non-purulent conjunctivitis) and with local PUVA (including blistering, erythema, and pruritus). With regard to the systemic retinoid alitretinoin, one trial (33 participants; moderate-quality evidence) showed that alitretinoin probably makes little or no difference in reducing severity when compared to placebo (RR 0.69, 95% CI 0.36 to 1.30). A similar number of adverse events were reported in both treatment groups, including headache, cheilitis, nausea, arthralgia, and nasopharyngitis (RR 0.84, 95% CI 0.61 to 1.17). Clearance was not reported. There may be little or no difference between etanercept and placebo in achieving clearance (RR 1.64, 95% CI 0.08 to 34.28; 1 study; 15 participants; low-quality evidence); however, the 95% CI was very wide, showing there may be a difference between groups. Severity was not measured. More patients treated with placebo may achieve reduced severity than those treated with ustekinumab, but the wide 95% CI indicates there might be little or no difference between groups and there might be greater effect with ustekinumab (RR 0.48, 95% CI 0.11 to 2.13; 1 study; 33 participants; low-quality evidence). Clearance was not reported. It is uncertain whether guselkumab increases clearance when compared to placebo (2 studies; 154 participants) because the quality of evidence is very low, but guselkumab probably better reduces disease severity (RR 2.88, 95% CI 1.24 to 6.69; 1 study; 49 participants; moderate-quality evidence). Secukinumab is probably superior to placebo in reducing severity (RR 1.55, 95% CI 1.02 to 2.35; 1 study; 157 participants; moderate-quality evidence), but our clearance outcome was not reported. None of these trials reported on occurrence of adverse effects. Only two of the studies discussed above reported adverse effects serious or severe enough to cause withdrawal. Guselkumab may cause more serious adverse events when compared to placebo, but there is uncertainty due to the very wide 95% CI showing there may be little or no difference and showing more events with placebo (RR 2.88, 95% CI 0.32 to 25.80; 1 study; 49 participants; low-quality evidence). Secukinumab probably causes more serious adverse events than placebo (RR 3.29, 95% CI 1.40 to 7.75; 1 study; 157 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS Evidence is lacking for major chronic palmoplantar pustulosis treatments such as superpotent corticosteroids, phototherapy, acitretin, methotrexate, and ciclosporin. Risk of bias and imprecision limit our confidence. Maxacalcitol may be more effective than placebo in achieving clearance in the short term (low-quality evidence), and the risk of adverse effects is probably similar (moderate-quality evidence). Oral alitretinoin is probably no more effective than placebo in reducing severity, with a similar risk of adverse effects (moderate-quality evidence). Regarding biological treatments, we are uncertain of the effect of etanercept on clearance and the effect of ustekinumab on severity (low-quality evidence). Secukinumab and guselkumab are probably superior to placebo in reducing severity (moderate-quality evidence). Adverse events not requiring withdrawal were not reported for these treatments. Reporting of serious adverse effects was incomplete: compared to placebo, secukinumab probably caused more participant withdrawals (moderate-quality evidence), but we are uncertain of the effect of guselkumab (low-quality evidence). Future trials should assess commonly used treatments using validated severity and quality of life scales.
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PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease.
Schmidt, AF, Carter, JL, Pearce, LS, Wilkins, JT, Overington, JP, Hingorani, AD, Casas, JP
The Cochrane database of systematic reviews. 2020;(10):CD011748
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Abstract
BACKGROUND Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk. OBJECTIVES Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention. SEARCH METHODS We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017. SELECTION CRITERIA All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible. DATA COLLECTION AND ANALYSIS Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables. MAIN RESULTS We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence). Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke. AUTHORS' CONCLUSIONS The evidence for the clinical endpoint effects of evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials. The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
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Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis.
Khan, SU, Riaz, H, Rahman, H, Khan, MU, Khan, MS, Alkhouli, M, Kaluski, E, Leucker, TM, Blaha, MJ
Journal of clinical lipidology. 2019;(4):538-549
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BACKGROUND The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy. METHODS In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL). RESULTS In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81-1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75-1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20-0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94-0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51-0.87) (P-interaction = .006). CONCLUSION PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.
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Cardiovascular safety of tocilizumab: A systematic review and network meta-analysis.
Castagné, B, Viprey, M, Martin, J, Schott, AM, Cucherat, M, Soubrier, M
PloS one. 2019;(8):e0220178
Abstract
OBJECTIVES Our objective was to compare the cardiovascular safety of tocilizumab and other biological disease-modifying antirheumatic drugs (bDMARD) in rheumatoid arthritis using a network meta-analysis (NMA). METHODS A systematic literature search through May 2018 identified randomized controlled trials (RCT) or observational studies (cohort only) reporting cardiovascular outcomes of tocilizumab (TCZ) and/or abatacept (ABA) and/or rituximab (RTX) and/or tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis patients. The composite primary outcome was the rate of major adverse cardiovascular outcomes (MACE, myocardial infarction (MI), peripheral artery disease (PAD) and cardiac heart failure (CHF)). RESULTS 19 studies were included in the NMA, including 11 RCTs and 8 cohort studies. We found less events with RTX (5.41 [1.70;17.26]. We found no difference between TCZ and other treatments. Concerning MI, we found no difference between TCZ and csDMARD (4.23 [0.22;80.64]), no difference between TCZ and TNFi (2.00 [0.18;21.84]). There was no difference between TCZ and csDMARD (1.51[0.02;103.50] and between TCZ and TNFi (1.00 [0.06;15.85]) for stroke event. With cohorts and RCT NMA, we found no difference between TCZ and other treatments for MACE (0.66 [0.42;1.03] with ABA, 1.04 [0.60;1.81] with RTX, 0.78[0.53;1.16] and 0.91 [0.54;1.51] with csDMARD), but the risk of myocardial infarction was lower with TCZ compared to ABA (0.67 [0.47;0.97]). We lacked data to compare TCZ and other bDMARD for stoke and MI. Not enough data was available to perform a NMA for CHF and PAD. CONCLUSIONS Despite an increase in cholesterol levels, TCZ has safe cardiovascular outcomes compared to other bDMARD.
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Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis.
Manohar, S, Kompotiatis, P, Thongprayoon, C, Cheungpasitporn, W, Herrmann, J, Herrmann, SM
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019;(1):108-117
Abstract
BACKGROUND The aim of this meta-analysis was to assess the risks and incidence of nephrotoxicity and electrolyte abnormalities in patients receiving programmed cell death protein 1 (PD-1) inhibitors. METHODS We conducted a meta-analysis of clinical trials that monitored electrolyte levels and kidney functions during treatment with nivolumab or pembrolizumab by searching MEDLINE, EMBASE and the Cochrane Database from inception through April 2017. Our protocol is registered with International Prospective Register of Systematic Reviews; no.CRD42017060579. RESULTS A total of 48 clinical trials with a total of 11 482 patients were included. The overall pooled risk ratios (RR) of all acute kidney injury (AKI) and all electrolyte abnormalities in patients treated with PD-1 inhibitors were 1.86 [95% confidence interval (CI) 0.95-3.64] and 1.67 (95% CI 0.89-3.12), respectively. Compared with non-nephrotoxic controls, the pooled RR of AKI in patients treated with PD-1 inhibitors was 4.19 (95% CI 1.57-11.18). Prespecified subgroup analyses demonstrated a significant association between PD-1 inhibitors and hypocalcemia with a pooled RR of 10.87 (95% CI 1.40-84.16). The pooled estimated incidence rates of AKI and hypocalcemia in patients treated with PD-1 inhibitors were 2.2% (95% CI 1.5-3.0%) and 1.0% (95% CI 0.6-1.8%), respectively. Among patients who developed AKI with PD-1 inhibitors, the pooled estimated rate of interstitial nephritis was 16.6% (95% CI 10.2-26.0%). CONCLUSIONS Treatment with PD-1 inhibitors is associated with a higher risk of AKI compared with non-nephrotoxic agents. It will be important to characterize the AKI patients to better understand the etiology behind the event. In addition, treatment with PD-1 inhibitors is associated with an increased risk of hypocalcemia. This study highlights a rare but serious adverse event of anti-PD-1 antibodies and we recommend, in addition to electrolytes panel, routine calcium monitoring.
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Effects of PCSK9 inhibitors on LDL cholesterol, cardiovascular morbidity and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.
Dicembrini, I, Giannini, S, Ragghianti, B, Mannucci, E, Monami, M
Journal of endocrinological investigation. 2019;(9):1029-1039
Abstract
BACKGROUND AND AIMS Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors determine a wide reduction of LDL cholesterol, greater than other lipid-lowering agents. The present meta-analysis is aimed at the assessment of PCSK9 inhibitors effect on LDL Cholesterol, cardiovascular morbidity and all-cause mortality. METHODS AND RESULTS A Medline and Clinicaltrials.gov search for eligible studies until December 1, 2017, was performed. All randomized trials (> 12 weeks) comparing PCSK-9 inhibitors with placebo or active drugs were retrieved. Primary endpoints: (a) LDL cholesterol at endpoint; (b) Major cardiovascular events (MACE); (c) All-cause mortality. Data extraction was performed independently by two of the authors, and conflicts resolved by a third investigator. A total of 38 trials fulfilling the inclusion criteria were identified, with mean duration of 36.4 weeks. The reduction of LDL cholesterol at endpoint, versus placebo, ezetimibe, and high-dose statins was - 65.3 [- 69.6, - 60.9]%, - 57.7 [- 68.3;- 47.0]%, and - 34.5 [- 40.8;- 28.1]%, respectively, with alirocumab possibly showing a smaller effect than the other drugs of the class. Treatment with PCSK9 inhibitors was associated with a reduction in the incidence of MACE (Mantel-Haenszel Odds Ratio [MH-OR] 0.83 [0.78, 0.88]), with significant effects of alirocumab and evolocumab only. The number needed to treat for 2 years for preventing one event was 89. All-cause mortality and cardiovascular mortality were not reduced by treatment with PCSK-9 inhibitors (MH-OR 0.94 [0.84, 1.04] and 0.97[0.86;1.09]). CONCLUSIONS PCSK-9 inhibitors are effective in reducing LDL cholesterol and the incidence of major cardiovascular events in high-risk patients. Bococizumab does not show significant effects on MACE. REGISTRATION NUMBER PROSPERO-CRD42018087640.
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Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review.
Abdel-Rahman, O
Immunotherapy. 2016;(12):1383-1391
Abstract
AIM: Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC). OBJECTIVE To assess the efficacy and safety of different dose schedules of pembrolizumab in the treatment of patients with advanced NSCLC and melanoma. Search method: MEDLINE database has been searched. Reference lists of original studies and review articles were checked for other related articles. SELECTION CRITERIA Prospective clinical trials reporting the outcomes of more than one dose schedule of pembrolizumab in the treatment of advanced NSCLC and melanoma. DATA COLLECTION & ANALYSIS The review author extracted information on the outcomes of the study for this review, and presented the results. MAIN RESULTS Four trials with 3425 patients were included in this systematic review. Pooled analysis for the odds ratio of objective response rate comparing 2 versus 10 mg/kg every 3 weeks in advanced melanoma was 1.03 (95% CI: 0.71-1.49; p = 0.89), while for advanced NSCLC, it was 0.97 (95% CI: 0.66-1.43; p = 0.87). Moreover, odds ratio for selected side effects between the two doses was as follows: rash: 0.83 (95 CI: 0.58-1.18; p = 0.29); vitiligo: 1.27 (95% CI: 0.62-2.61; p = 0.52); diarrhea: 0.94 (95% CI: 0.63-1.42; p = 0.79); hypothyroidism: 0.97 (95% CI: 0.63-1.50; p = 0.90); hepatitis/elevated transaminases: 1.86 (95% CI: 0.91-3.79; p = 0.09); nephritis: 0.88 (95% CI: 0.32-2.44; p = 0.80); pneumonitis: 1.17 (95% CI: 0.62-2.23; p = 0.63). CONCLUSIONS Given the equivalence in efficacy and safety between lower doses and higher doses of pembrolizumab, 2 mg/kg every 3 weeks seems to be an appropriate dose for routine practice in advanced pretreated NSCLC and melanoma.