Abstract
Rethinking pulmonary vascular resistance in pulmonary arterial hypertensionhttps://bit.ly/2RmnTDw
Clinical outcomes in pulmonary arterial hypertension (PAH) have improved substantially in the modern era, owing to greater clinician awareness, availability of numerous pulmonary vasodilator therapies and, now, more than two decades of sound clinical trial data informing optimal strategies for treating patients [1]。This arc of progress began with therapeutic interventions that aimed to simply delay mortality in patients with end-stage disease, at a time in which PAH was regarded as by-and-large uniformly fatal. The evolution of PAH into a contemporary and treatable disease has been marked by specific sentinel transition points, including proven efficacy of prescription exercise, sequential add-on treatment with different drug classes, and up-front combination therapy in newly diagnosed patients [2]。这导致了在临床实践中定义治疗成功的大大增强目标的集体转变,例如症状负担,保存的运动耐受性和良好的血液动力学参数[3]。
In line with this trend, early PAH diagnosis has emerged as the next major front in the battle to optimise quality of life, decrease morbidity and improve upon hard clinical event rates that remain unacceptably elevated. This emphasis coincides with accumulating clinical and epidemiological research findings suggesting that opportunities may exist to refine the haemodynamic criteria defining pulmonary hypertension, generally, and PAH, specifically [4,5]。Indeed, the upper limit of normal mean pulmonary artery pressure (mPAP) converges with data showing that decreased functional capacity and increased mortality in patients at risk for PAH begins at ∼20 mmHg [6]。To modernise clinical practice, the 6th World Symposium on Pulmonary Hypertension (Nice, France) recommended changing the mPAP threshold defining PAH from ≥25 mm to >20 mmHg [7]。
该修订的主要目标是捕获早期PAH的患者,目前诊断和管理被忽视。重要的是,肺血管抗性(PVR)的增加至少部分地通过肺部动脉源的葡萄球菌,纤维化和肥大侵蚀是PAH的标志特征[2]。Yet, patients with mildly elevated mPAP are unlikely to meet the PVR threshold of >3.0 WU used to diagnose PAH currently, derived mainly from historical consensus opinion [8]。因此,修改MPAP阈值至> 20mmHg也建立了需要澄清最佳PVR用于诊断PAH,包括早期(温和)疾病。在PAH中完成这一目标将需要绘制框架的PVR值,这些PVR值是规范性的,致病性和对治疗的有利反应相关的。
In this issue of theEuropean Respiratory Journal, Ratwatteet al.[9] add a key piece to the PVR puzzle by leveraging the unique clinical practice patterns in Australian and New Zealand, in which PVR ≥3.0 WU is not obligatory for treating PAH. The investigators assembled data for 2378 PAH patients enrolled in the PHSANZ registry between 2011 and 2018, and focused on 82 patients for whom the PVR was <3.0 WU. This subgroup had the following haemodynamic profile (medians presented with interquartile ranges): PVR 2.2 (1.9–2.7) WU, mPAP 27 (IQR 25–30) mmHg, pulmonary artery wedge pressure 13 (11–14) mmHg. All patients were prescribed at least an endothelin receptor antagonist (80.4%) or phosphodiesterase type-V inhibitor (19.5%), and 17% were on dual therapy. After a median follow-up of 5 months, 6-min walk distance increased on average by 46 m and one-third of patients improved ≥1.0 New York Heart Association functional class, with greater effects observed in idiopathic rather than connective tissue disease-associated PAH.
Beyond these findings suggesting salutatory clinical benefit for the study population in the early phase of treatment, some important insights were gained during the long-term follow-up spanning a median 65 months after diagnosis. First, the PVR progressed to >3.0 WU in seven (27%) of the 26 patients undergoing repeat right heart catheterisation at 1 year. This suggests that for some patients, PVR progresses to levels classically associated with PAH (i.e.≥3.0 WU) soon after diagnosis, and this vulnerable subgroup may be captured earlier when considering a PVR range beginning ∼2.2 WU. Second, the 3-year and 5-year survival rates for the study population were 89% and 83%, respectively, which are more favourable than for other real-world outcome data in PAH populations, including from studies with only dual therapy patients [10]。Taken together, these data begin an important narrative exploring potential opportunity to affect outcome in PAH when considering a PVR threshold <3.0 WU.
随着作者主张的,研究人口是独一无二的,但规模谦虚;当与回顾性的研究设计相结合时,这可能会限制对其他PAH群体的研究结果的可延长性。此外,该研究的结果不阐明最佳的心肺血管动力学光谱以限定PAH,或者应该用于引发治疗的方法。实际上,MPAP 21-24 mmHg的患者现在包括在现代PAH定义中,不是目前研究的一部分。然而,值得注意的是,PVR〜2.0-2.2吴已被描述为正常的上限[5],并与大未选择的人群中的临床事件增加有关[11] and connective tissue disease patients [12]。Nevertheless, data from this study are not ready for use in clinical practice, which as the authors clearly state will require further rigorous prospective investigations clarifying how best to interpret PVR <3.0 WU at point-of-care. Results extrapolated from this study could also be used to guide national screening programmes for detecting early stage PAH, already underway in some countries, including France [13]。
Ratwatteet al.[9]应祝贺这些重要数据,这有助于建立一种急需的框架,以便与PVR同时调整PAH血管动力学标准。这些调查结果应使用明确的临床研究方法刺激额外的调查,这些方法在当前工作时尚未获得,以了解PVR <3.0吴和PAH治疗反应之间的关联。正是这种方式,该领域朝着进一步改善临床结果,可能是预防性药物的时代。
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Conflict of interest: B.A. Maron receives research funding from the NIH (NIH U01HL125215-01; R21HL134320; 1R01HL139613-01; U54HL119145), Cardiovascular Medical Research Education Foundation, and Boston Biomedical Innovation Center; is a co-inventor on US patent 9 605 047, US pending patent PCT/US2019/059890, and provisional patent applications 62475955 and 029672; and is a member of the steering committee for a research grant supported by Actelion Pharmaceuticals, outside the submitted work.
兴趣冲突:M. Humbert报告了Pacelion,Bayer,GSK和Acceleron的赠款和个人费用,来自Merck和United Therapeutics的个人费用,在提交的工作之外。
支持声明:B.A.Maron从NIH获得研究资金(NIH U01H1125215-01; R21HL134320; 1R01HL11913-01; U54HL119145; R01HL153502),心血管医学研究教育基金会和波士顿生物医学创新中心。本文的资金信息已存入Crossref Funder Registry.
- 收到April 1, 2020.
- Accepted2020年4月2日。
- 复制right ©ERS 2020