Ghebremariam Yohannes T, Cooke John P, Khan Fouzia, Thakker Rahul N, Chang Peter, Shah Nigam H, Nead Kevin T, Leeper Nicholas J
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Vasc Med. 2015 Aug;20(4):309-16. doi: 10.1177/1358863X14568444. Epub 2015 Apr 2.
Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross-over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = -0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies.
质子泵抑制剂（PPIs）是治疗胃反流的常用药物。最近的回顾性队列研究和大型数据库研究引发了人们对使用PPIs与心血管（CV）风险增加相关的担忧。然而，尚无前瞻性临床研究评估PPIs的使用是否直接导致心血管损害。我们对21名18岁及以上的成年人进行了一项对照、开放标签、交叉试点研究，这些成年人健康（n = 11）或已确诊临床心血管疾病（n = 10）。研究对象被分配每天服用一次PPI（兰索拉唑；30毫克）或安慰剂，持续4周。经过2周的洗脱期后，参与者交叉接受接下来4周的替代治疗。在每个治疗间隔前后，受试者接受血管功能评估（采用EndoPAT技术），并测量血浆不对称二甲基精氨酸（ADMA，一种先前与PPI介导的风险有关的内皮功能内源性抑制剂）水平。我们观察到EndoPAT评分与血浆ADMA水平之间存在微弱的负相关（r = -0.364）。与服用安慰剂相比，服用PPI的受试者血浆ADMA水平恶化更明显，且这种趋势在有血管疾病史的受试者中更为显著。然而，这些趋势未达到统计学意义，在本研究过程中，PPI的使用也与血流介导的血管舒张功能受损无关。总之，在这项针对健康受试者和冠心病患者进行的开放标签、交叉试点研究中，PPI的使用并未显著影响血管内皮功能。需要进行更大规模、长期且双盲的试验，以从机制上解释PPI使用与不良临床结局之间的相关性，这一相关性最近在回顾性队列研究中已有报道。
