背景:血管紧张素转换酶抑制剂(ACEi)和血管紧张素受体阻滞剂(ARB)药物被广泛使用。我们试图评估在血管舒张性休克期间入院前使用这些药物可能如何影响对血管紧张素II治疗的反应。
方法:在随机分组的事后亚组分析中,安慰剂对照,血管紧张素治疗高输出休克(ATHOS-3)试验,我们比较了使用慢性血管紧张素转换酶抑制剂(ACEi)的患者,和使用血管紧张素受体阻滞剂(ARB)的患者,不接触ACEi或ARB的患者。主要结果是治疗1小时后的平均动脉压。其他临床结果包括随着时间的推移平均动脉压和去甲肾上腺素等效剂量要求,随着时间的推移和研究药物剂量。生物学结果包括基线RAS生物标志物(肾素,血管紧张素-I,血管紧张素II,和血管紧张素-I/血管紧张素-II比率),以及肾素从0到3小时的变化。
结果:我们包括n=321名患者,谁,270名ACEi和ARB未暴露,29例暴露于ACEi,22例暴露于ARB。在ACEi/ARB未暴露的患者中,血管紧张素治疗的患者,与安慰剂相比,1小时平均动脉压较高(9.1mmHg[95%CI7.6-10.1],p<0.0001),在48小时内降低去甲肾上腺素等效剂量(p=0.0037),和较低的研究药物剂量超过48小时(p<0.0001)。与未暴露的ACEi/ARB相比,接受血管紧张素II治疗的ACEi暴露患者的1小时平均动脉压相似(治疗效果差异:-2.2mmHg[95%CI-7.0-2.6],pinteraction=0.38),但在48小时内,去甲肾上腺素等效剂量(p相互作用=0.0031)和研究药物剂量(p相互作用<0.0001)的减少更大。相比之下,与未暴露的ACEi/ARB相比,暴露于ARB的患者对1小时平均动脉压的血管紧张素II的作用减弱(治疗效果差异:-6.0mmHg[95%CI-11.5至-0.6],pinteraction=0.0299),去甲肾上腺素等效剂量(pinteraction<0.0001),和研究药物剂量(p相互作用=0.0008)。ACEi暴露患者的基线肾素水平和血管紧张素-I/血管紧张素-II比率最高。最后,在ACEi/ARB未暴露和ACEi暴露的患者中,血管紧张素II治疗降低了h-3肾素,但在ARB暴露的患者中没有降低.
结论:在血管舒张性休克患者中,对血管紧张素-II的心血管和生物学RAS反应因之前服用ACEi和ARB药物而有所不同.ACEi暴露与血管紧张素II反应性增加有关,而ARB暴露与反应性降低相关。这些发现对血管舒张性休克患者的选择和血管紧张素II的剂量具有临床意义。试验注册临床试验。政府标识符:NCT02338843(2015年1月14日注册)。
Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock.
In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h.
We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients.
In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).