Crizanlizumab and comparators for adults with sickle cell disease: a systematic review and network meta-analysis - PubMed (original) (raw)
Crizanlizumab and comparators for adults with sickle cell disease: a systematic review and network meta-analysis
Howard Thom et al. BMJ Open. 2020.
Abstract
Objectives: Treatment options for preventing vaso-occlusive crises (VOC) among patients with sickle cell disease (SCD) are limited, especially if hydroxyurea treatment has failed or is contraindicated. A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the efficacy and safety of crizanlizumab for older adolescent and adult (≥16 years old) SCD patients.
Methods: The SLR included randomised controlled trials (RCTs) and uncontrolled studies. Bayesian NMA of VOC, all-cause hospitalisation days and adverse events were conducted.
Results: The SLR identified 51 studies and 9 RCTs on 14 treatments that met the NMA inclusion criteria. The NMA found that crizanlizumab 5.0 mg/kg was associated with a reduction in VOC (HR 0.55, 95% credible interval (0.43, 0.69); Bayesian probability of superiority >0.99), all-cause hospitalisation days (0.58 (0.50, 0.68); >0.99) and no evidence of difference on adverse events (0.91 (0.59, 1.43) 0.66) or serious adverse events (0.93 (0.47, 1.87); 0.59) compared with placebo. The HR for reduction in VOC for crizanlizumab relative to L-glutamine was (0.67 (0.50, 0.88); >0.99). These results were sensitive to assumptions regarding whether patient age is an effect modifier.
Conclusions: This NMA provides preliminary evidence comparing the efficacy of crizanlizumab with other treatments for VOC prevention.
Keywords: crizanlizumab; hematology; network meta-analysis; sickle cell disease; systematic literature review; vasoocclusive crisis.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Conflict of interest statement
Competing interests: Novartis reviewed the manuscript prior to submission. JS and JJ disclose employment by and equity in by precision HEOR, a consulting firm to the life sciences and broader health care industry. HT discloses personal consulting fees from Novartis Pharma AG, Hoffman La-Roche, Pfizer and Eli Lilly. LZ discloses employment by precision HEOR, a consulting firm to the life sciences and broader health care industry. NS discloses research funding and speaker fees from Novartis Pharmaceutical Company.
Figures
Figure 1
SCD prisma flow chart. NMA, network meta-analysis; SCD, sickle cell disease.
Figure 2
Evidence networks. Each node represents a treatment and nodes are connected by an edge if at least trial has compared the relevant treatments. Any two treatments can be compared if their corresponding nodes can be connected by a path of one or more edges. High-dose crizanlizumab=5 mg/kg 14 times over 52 weeks. Low-dose crizanlizumab=2.5 mg/kg 14 times over 52 weeks. High-dose ticagrelor=two times per day 45 mg, low-dose ticagrelor=two times per day 10 mg; low-dose NAC=N-acetylcysteine 600 mg, mid-dose NAC=N-acetylcysteine 1200 mg, high-dose NAC=N-acetylcysteine 2400 mg; senicapoc=loading dose of 20 mg two times per day for 4 days followed by 10 mg daily maintenance, low-dose senicapoc=single loading dose of 100 mg followed by maintenance 6 mg daily, high-dose senicapoc=single loading dose of 150 mg followed by maintenance 10 mg daily. Five RCTs on crisis=Ataga et al, 2017 (crizanlizumab vs placebo), Niihara et al (L-glutamine vs placebo), Ataga et al, 2011 (senicapoc vs placebo), Ataga et al, 2008 (senicapoc low-dose, senicapoc high-dose vs placebo) and Pace et al (NAC low, mid and high dose vs placebo). Four RCTs on all-cause hospitalisation days=Ataga et al, 2017 (crizanlizumab vs placebo), Niihara et al (L-glutamine vs placebo), Glassberg et al (mometasone vs placebo) and Sins et al (NAC vs placebo). Five RCTs on adverse events=Glassberg et al (mometasone vs placebo), Ataga et al, 2017 (crizanlizumab vs placebo), Ataga et al, 2011 (senicapoc vs placebo), Sins et al (NAC vs placebo) and Niihara et al (L-glutamine vs placebo). Five RCTs on serious adverse events=Ataga et al, 2017 (crizanlizumab vs placebo), Sins et al (NAC vs placebo), Wun et al (prasugrel vs placebo), NCT02482298 (TICAGRELOR vs placebo) and Niihara et al (L-glutamine vs placebo). RCTs, randomised controlled trials; VOC, vaso-occlusive crises.
Figure 3
Forest plot. HR <1 suggests lower hazard of event on the crizanlizumab. Bayesian probabilities of superiority are proportion of MCMC samples for which crizanlizumab vs comparator HR is above (inferior) or below (superior) 1. High-dose crizanlizumab=5 mg/kg 14 times over 52 weeks. Low-dose crizanlizumab=2.5 mg/kg 14 times over 52 weeks. High-dose ticagrelor=two times per day 45 mg, low-dose ticagrelor=two times per day 10 mg; low-dose NAC=N-acetylcysteine 600 mg, mid-dose NAC=N-acetylcysteine 1200 mg, high-dose NAC=N-acetylcysteine 2400 mg; senicapoc=loading dose of 20 mg two times per day for 4 days followed by 10 mg daily maintenance, low-dose senicapoc=single loading dose of 100 mg followed by maintenance 6 mg daily, high-dose senicapoc=single loading dose of 150 mg followed by maintenance 10 mg daily. MCMC, Markov chain Monte Carlo; VOC, vaso-occlusive crises.
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