Background

The hemodynamic impact of persistent patent ductus arteriosus (PDA) is associated with neonatal morbidities and mortality in preterm newborns. While there has been considerable debate about optimal management of PDA and its impact on clinical outcomes, there is widespread variation in practice, such as using different pharmacotherapies to achieve closure of hemodynamically significant PDA during the first week of life in very low birth weight infants.

Aims

The objective was to estimate the efficacy of acetaminophen, ibuprofen, and indomethacin with regard to ductal closure and to compare the costs of these three commonly used medications to treat PDA in preterm infants.

Methods

PubMed, Embase, and Cochrane Registry were searched for trials from the years 2010–2020. We identified 17 randomized clinical trials (RCTs) and 14 case series that enrolled preterm infants < 37 weeks gestational age for inclusion. Pooled estimates of closure rates for acetaminophen (n = 630), ibuprofen (n = 694), and indomethacin (n = 312) were analyzed using the weighted proportion ratio using a Mantel‑Haenszel random effects model. The chi-squared test of proportions was used to determine significance between groups. We accessed cost estimates of pharmacotherapy from the Lexi-Comp average wholesale price database and utilized a decision tree model to appraise cost benefits for the outcome measure of successful PDA closure.

Results

The pooled proportional point estimates of closure rates from RCTs for acetaminophen, ibuprofen, and indomethacin were 70.1% (95% confidence interval [CI] 60–80), 63.4% (95% CI 52.8–74.1), and 71.5% (95% CI 62.3–80.7), respectively. There was no significant statistical difference in closure rates when RCTs and uncontrolled case series were combined. Pairwise comparisons showed both acetaminophen and indomethacin were each more effective in closing PDA than ibuprofen (acetaminophen vs indomethacin: p = 0.01; ibuprofen vs indomethacin: p = 0.02; acetaminophen vs indomethacin: p = 0.93). Comparing costs for successful closure of PDA, at the average wholesale price of different medications, suggested that treatment with acetaminophen costs significantly less, with a mean of $1487 (95% CI 1300–1737), compared to ibuprofen, with a mean of $2585 (95% CI 2214–3104), and indomethacin, with a mean of $2661 (95% CI 2358–3052), per course of treatment.

Conclusions

Our meta-analysis suggests acetaminophen is non-inferior to both indomethacin and ibuprofen, and costs relatively less for successful PDA constriction in premature infants. Further clinical trials are warranted to compare acetaminophen’s safety, along with short- and long-term effects, to help resolve the clinical conundrum of the necessity of early treatment in the management of PDA, and the optimal pharmacological course, if indicated.

中文翻译：

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三种药物治疗早产儿动脉导管未闭的疗效和费用

背景

持续性动脉导管未闭 (PDA) 对血流动力学的影响与早产儿的新生儿发病率和死亡率有关。尽管关于 PDA 的最佳管理及其对临床结果的影响存在相当大的争论，但实践中存在广泛的差异，例如在极低出生体重婴儿出生后的第一周使用不同的药物疗法来关闭具有血流动力学意义的 PDA。

目标

目的是评估对乙酰氨基酚、布洛芬和消炎痛在导管闭合方面的疗效，并比较这三种常用药物治疗早产儿 PDA 的成本。

方法

PubMed、Embase 和 Cochrane Registry 检索了 2010-2020 年的试验。我们确定了 17 项随机临床试验 (RCT) 和 14 个病例系列，纳入了胎龄小于 37 周的早产儿。对乙酰氨基酚 ( n = 630)、布洛芬 ( n = 694) 和消炎痛 ( n = 312)的闭合率的汇总估计值使用 Mantel-Haenszel 随机效应模型使用加权比例比进行分析。比例的卡方检验用于确定组间的显着性。我们从 Lexi-Comp 平均批发价格数据库中获取了药物治疗的成本估算，并利用决策树模型来评估成功关闭 PDA 的结果测量的成本效益。

结果

对乙酰氨基酚、布洛芬和消炎痛的 RCT 关闭率的汇总比例点估计值为 70.1%（95% 置信区间 [CI] 60-80）、63.4%（95% CI 52.8-74.1）和 71.5%（95% CI 62.3–80.7)，分别。当 RCT 和非对照病例系列相结合时，关闭率没有显着的统计学差异。成对比较显示，对乙酰氨基酚和吲哚美辛在关闭 PDA 方面均比布洛芬更有效（对乙酰氨基酚 vs 吲哚美辛：p = 0.01；布洛芬 vs 吲哚美辛：p = 0.02；对乙酰氨基酚 vs 吲哚美辛：p= 0.93)。以不同药物的平均批发价格比较成功关闭 PDA 的费用表明，与布洛芬的平均费用为 2585 美元相比，用对乙酰氨基酚治疗的费用显着降低，平均为 1487 美元（95% CI 1300-1737）。 95% CI 2214–3104) 和消炎痛，平均每个疗程 2661 美元 (95% CI 2358–3052)。

结论

我们的荟萃分析表明，对乙酰氨基酚不劣于消炎痛和布洛芬，并且在早产儿成功收缩 PDA 的成本相对较低。需要进一步的临床试验来比较对乙酰氨基酚的安全性以及短期和长期效果，以帮助解决在 PDA 管理中早期治疗的必要性以及最佳药理学过程（如果有指征）的临床难题。