Desmopressin and the risk of hyponatremia: A population-based cohort study
Desmopressin and the risk of hyponatremia: A population-based cohort study
复制标题
DOI：
10.1371/journal.pmed.1002930
复制
发表时间：
2019-10-01
期刊：
影响因子：
15.8
通讯作者：
Kesselheim, Aaron S.
中科院分区：
文献类型：
--
作者：
Fralick, Michael;Schneeweiss, Sebastian;Kesselheim, Aaron S.
背景去氨加压素于1978年被美国食品和药物管理局（FDA）批准用于治疗尿崩症和出血性疾病，但它也被用于治疗尿崩症患者。量化成年患者服用去氨加压素的潜在风险变得更加重要，因为FDA在2017年批准了一种新的去氨加压素鼻内制剂。与旧配方一样，主要活性成分是醋酸去氨加压素，但新配方还含有旨在增强吸收的赋形剂。我们的目的是量化低钠血症的发生率在常规临床护理的患者处方的老配方的去氨加压素。方法和发现我们于2006年2月1日至2017年2月1日使用全国商业健康计划数据库进行了一项基于人群的新用户队列研究。新处方的老配方去氨加压素的患者倾向评分（PS）匹配的患者新处方奥昔布宁。作为敏感性分析，使用坦索罗辛而不是奥昔布宁作为对照药物。主要结局是低钠血症的初步定位诊断。使用1：1 PS匹配后的比例风险模型估计风险比（HR）和95%置信区间（CI）。我们确定了3,137名新处方去氨加压素的成年人，并将他们与3,137名新处方奥昔布宁的成年人进行了匹配。平均年龄为70岁，55%为男性，13%在基线期间服用利尿剂处方，接受任一研究药物前的平均基线钠为140 mmol/L（正常：135-145）。使用去氨加压素的成人患者的低钠血症发生率为146/1000人-年，而使用奥昔布宁的成人患者的低钠血症发生率为11/1000人-年，相当于高13倍（HR 13.19; 95% CI 6.69，26.01; p < 0.01）。当随访在30天时截短时，观察到类似的增加率（HR 19.41; 95% CI 7.11，52.99; p < 0.01）。当坦索罗辛作为对照药物时，去氨加压素也观察到更高的低钠血症发生率（HR 12.10; 95% CI 6.54，22.37; p < 0.01）。我们研究的重要局限性包括未测量的混杂因素（例如，非处方药使用，饮食摄入），缺失数据（即，只有20%的患者具有基线血清钠），以及缺乏关于去氨加压素新制剂的数据。结论：与使用其他治疗下尿路症状的药物相比，使用较老剂型的去氨加压素与随后低钠血症的发生率显著增加相关。这样的风险应该清楚地传达给病人处方这种制剂的desmopressin.Author summaryWhy是这项研究做？去氨加压素是一种有时用于夜间多次醒来排尿的成年人的药物，即使它以前没有被美国食品和药物管理局（FDA）批准用于此目的。去氨加压素的一个潜在风险是低钠水平（也称为低钠血症），这可能危及生命。研究人员做了什么，发现了什么？我们使用美国国家医疗保健数据库进行了一项研究，观察到较旧的去氨加压素制剂会增加低钠血症的风险。去氨加压素组低钠血症的发生率为146/1000人-年，而奥昔布宁组为11/1000人-年。这些发现意味着什么？在处方这种较旧的去氨加压素制剂之前，应考虑低钠血症的潜在风险增加。FDA于2017年批准的去氨加压素新制剂的进一步观察性研究，其中含有与旧制剂相同的活性成分，以评估低钠血症的风险。
Background Desmopressin was approved by the Food and Drug Administration (FDA) in 1978 for use in diabetes insipidus and bleeding disorders, but it is also prescribed off-label for patients with nocturia. Quantifying the potential risks facing adult patients taking desmopressin has taken on added importance because a new intranasal formulation of desmopressin was approved by the FDA in 2017. Like the old formulation, the main active ingredient is desmopressin acetate, but the new formulation also contains an excipient designed to enhance absorption. Our objective was to quantify the rate of hyponatremia in routine clinical care for patients prescribed the older formulation of desmopressin. Methods and findings We conducted a population-based new-user cohort study from 1 February 2006 to 1 February 2017 using a nationwide commercial health plan database. Patients newly prescribed the older formulation of desmopressin were propensity-score (PS)-matched to patients newly prescribed oxybutynin. As a sensitivity analysis, tamsulosin was used as the comparator rather than oxybutynin. The primary outcome was a primary position diagnosis of hyponatremia. Proportional hazard models after 1:1 PS matching were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). We identified 3,137 adults who were newly prescribed desmopressin and matched them to 3,137 adults who were newly prescribed oxybutynin. Mean age was 70, 55% were male, 13% filled a prescription for a diuretic during the baseline time period, and the mean baseline sodium prior to receiving either study drug was 140 mmol/L (normal: 135-145). The rate of hyponatremia was 146 per 1,000 person-years for adults prescribed desmopressin compared to 11 per 1,000 person-years for adults prescribed oxybutynin, corresponding to a 13-fold higher rate (HR 13.19; 95% CI 6.69, 26.01; p < 0.01). When follow-up was truncated at 30 days, a similar increased rate was observed (HR 19.41; 95% CI 7.11, 52.99; p < 0.01). A higher rate of hyponatremia was also observed with desmopressin when tamsulosin was the comparator (HR 12.10; 95% CI 6.54, 22.37; p < 0.01). Important limitations of our study include unmeasured confounding (for example, over-the-counter medication use, dietary intake), missing data (i.e., only 20% of patients had a baseline serum sodium), and a lack of data on the newer formulation of desmopressin. Conclusions Use of an older formulation of desmopressin was associated with a marked increased rate of subsequent hyponatremia compared to use of other medications indicated for lower urinary tract symptoms. Such risks should be clearly communicated to patients prescribed this formulation of desmopressin.Author summaryWhy was this study done? Desmopressin is a medication that is sometimes used for adults who awake multiple times in the night to urinate, even though it was not previously approved for this purpose by the Food and Drug Administration (FDA). One potential risk of desmopressin is a low sodium level (also known as hyponatremia), which can be life-threatening. What did the researchers do and find? We conducted a study using a national healthcare database in the US and observed an increased risk of hyponatremia with the older formulation of desmopressin. The rate of hyponatremia was 146 per 1,000 person-years with desmopressin compared to approximately 11 per 1,000 person-years among patients who received oxybutynin. What do these findings mean? The potential increased risk of hyponatremia should be considered prior to prescribing this older formulation of desmopressin. Further observational study of the new formulation of desmopressin that was approved by the FDA in 2017, which contains the same active ingredient as the older formulation, to assess for the risk of hyponatremia is warranted.