Articles
Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: a retrospective cohort study

https://doi.org/10.1016/S2213-2600(20)30317-9Get rights and content

Summary

Background

In pulmonary hypertension subgroups, elevated pulmonary vascular resistance (PVR) of 3·0 Wood units or more is associated with poor prognosis. However, the spectrum of PVR risk in pulmonary hypertension is not known. To address this area of uncertainty, we aimed to analyse the relationship between PVR and adverse clinical outcomes in pulmonary hypertension.

Methods

We did a retrospective cohort study of all patients undergoing right heart catheterisation (RHC) in the US Veterans Affairs health-care system (Oct 1, 2007–Sep 30, 2016). Patients were included in the analyses if data from a complete RHC and at least 1 year of follow-up were available. Both inpatients and outpatients were included, but individuals with missing mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure, or cardiac output were excluded. The primary outcome measure was time to all-cause mortality assessed by the Veteran Affairs vital status file. Cox proportional hazards models were used to assess the association between PVR and outcomes, and the mortality hazard ratio was validated in a RHC cohort from Vanderbilt University Medical Center (Sept 24, 1998–June 1, 2016).

Findings

The primary cohort (N=40 082; 38 751 [96·7%] male; median age 66·5 years [IQR 61·1–73·5]; median follow-up 1153 days [IQR 570–1971]), included patients with a history of heart failure (23 201 [57·9%]) and chronic obstructive pulmonary disease (13 348 [33·3%]). We focused on patients at risk for pulmonary hypertension based on a mPAP of at least 19 mm Hg (32 725 [81·6%] of 40 082). When modelled as a continuous variable, the all-cause mortality hazard for PVR was increased at around 2·2 Wood units compared with PVR of 1·0 Wood unit. Among patients with a mPAP of at least 19 mm Hg and pulmonary artery wedge pressure of 15 mm Hg or less, the adjusted hazard ratio (HR) for mortality was 1·71 (95% CI 1·59–1·84; p<0·0001) and for heart failure hospitalisation was 1·27 (1·13–1·43; p=0·0001), when comparing PVR of 2·2 Wood units or more to less than 2·2 Wood units. The validation cohort (N=3699, 1860 [50·3%] male, median age 60·4 years [49·5–69·2]; median follow-up 1752 days [IQR 1281–2999]) included 2870 patients [77·6%] with mPAP of at least 19 mm Hg (1418 [49·4%] male). The adjusted mortality HR for patients in the mPAP of 19 mm Hg or more group and with PVR of 2·2 Wood units or more and pulmonary artery wedge pressure of 15 mm or less Hg (1221 [42·5%] of 2870) was 1·81 (95% CI 1·33–2·47; p=0·0002).

Interpretation

These data widen the continuum of clinical risk for mortality and heart failure in patients referred for RHC with elevated pulmonary artery pressure to include PVR of around 2.2 Wood units and higher. Testing the generalisability of these findings in at-risk populations with fewer cardiopulmonary comorbidities is warranted.

Funding

None.

Introduction

Elevated mean pulmonary artery pressure (mPAP) is the principal haemodynamic finding in pulmonary hypertension. The previous definition of pulmonary hypertension used mPAP of 25 mm Hg or more;1 however, historical data from healthy volunteers established mPAP around 19–20 mm Hg as the upper limit of normal,2 with values of less than 25 mm Hg corresponding to adverse prognosis in large referral populations for right heart catheterisation (RHC)3, 4 and among smaller well phenotyped pulmonary hypertension cohorts.5 This led to a pulmonary hypertension haemodynamic definition in 2019 that is contemporary, evidence-based, and includes mPAP values of more than 20 mm Hg.6

Elevated mPAP can be observed under certain physiological or immediately reversible conditions, and is not inherently pathognomonic for pulmonary vascular disease.7 Pulmonary vascular resistance (PVR) of 3·0 Wood units or more is used to prognosticate and guide clinical decision making in pulmonary arterial hypertension, primary obstructive lung disease, and orthotopic heart transplantation candidates, among other selected pulmonary hypertension subgroups.8, 9, 10 However, the upper limit of normal PVR can reach around 2·1 Wood units in some adult populations,11, 12 and post-hoc analyses from single-centre studies in patients with connective tissue disease imply that PVR values of less than 3·0 Wood units might be clinically relevant.13 Nonetheless, sufficiently powered studies focusing on the association between PVR and clinical risk in pulmonary hypertension are absent.

Research in context

Evidence before this study

We searched Medline using PubMed for all full text publications published from database inception to April 10, 2020, using the medical subject heading terms “pulmonary vascular resistance” and “pulmonary hypertension” and “mortality”, as well as the term “catheterisation” in any search field. We included studies in humans aged 19 years or older of the following types: clinical study, dataset, journal article, multicentre study, and observational study. Reviews, biographies, case reports, clinical trials, and non-academic article types or publications not in English were excluded. This search returned 38 publications; of these, two were determined to be case reports and 35 included highly selected clinical populations, such as patients with congenital heart disease, previous pneumothorax, or post-orthotopic heart transplant status. All of these reports included fewer than 320 patients and none included patients with mildly elevated pulmonary artery pressure using the revised haemodynamic definition of pulmonary hypertension. The remaining publication was a single-centre study of 4343 patients, and pulmonary vascular resistance (PVR) emerged from a multivariate analysis as a risk factor for mortality in patients that included (but was not exclusive of) mild pulmonary hypertension. In that study, the continuum of clinical risk associated with PVR was not reported. Overall, knowledge on the clinical significance of PVR in pulmonary hypertension has emphasised historical consensus opinion and data from small studies in selected populations analysing outcome differences using predefined definitions.

Added value of this study

To our knowledge, this study provides the first evidence-based assessment on the continuum of clinical risk associated with PVR in pulmonary hypertension, which is derived from a sufficiently powered national database of patients undergoing right heart catheterisation and validated in a second large patient cohort. This study also uses mortality and heart failure hospitalisation, which are disease-relevant outcomes, to determine the association between PVR and clinical risk using the revised pulmonary artery pressure criterion for pulmonary hypertension.

Implications of all the available evidence

Data from this study show that risk for adverse outcome associated with PVR in pulmonary hypertension emerges at around 2·2 Wood units, which is well below the PVR associated with the disease state in clinical practice. We identified patients with precapillary pulmonary hypertension at the time of right heart catheterisation as particularly vulnerable. Overall, these results suggest that reconsidering the haemodynamic parameters that define pulmonary hypertension in patients with cardiopulmonary disease is warranted, and they identify a need for early detection strategies to capture this large and vulnerable population.

The Veterans Affairs Clinical Assessment, Reporting, and Tracking (VA-CART) Program is a national quality and safety programme for invasive cardiac procedures within the VA Healthcare System in the USA. As such, the Program collects haemodynamic data from every patient who undergoes a RHC in any of the 81 cardiac catheterisation laboratories within this integrated health-care system. Furthermore, the CART Analytic Center is able to associate clinical and haemodynamic data to clinical outcomes, creating one of the largest cohorts containing longitudinal information on patients with pulmonary hypertension.2, 14, 15, 16 We leveraged the size of this database to analyse the association of PVR and mortality as well as hospital admission for heart failure in patients with elevated mPAP, with the aim of clarifying the clinical significance of PVR when considering the revised mPAP criterion for pulmonary hypertension diagnosis.6

Section snippets

Study design and participants

The details of the VA-CART Program and assembly of the RHC registry have been reported in detail previously.3, 17 Briefly, the VA-CART Program uses a software application embedded in the VA electronic health record for documentation of all cardiac catheterisation procedures. Key patient characteristics and procedural data were collected and tracked for longitudinal outcomes. Regularly scheduled quality checks of the CART data are done to ensure completeness and accuracy.

We evaluated all

Results

We identified 40 082 eligible VA-CART patient records from the 51 639 records assessed (77·6%), which formed the primary cohort. This primary cohort was largely male (n=38 751 [96·7%]) with a median age of 66·5 years (IQR 61·1–73·5) and frequent history of cardiopulmonary comorbidities (table 1). Previous data modelling with mPAP as a continuous variable showed that clinical risk increases began at around 19 mm Hg.3 We found mildly elevated mPAP (19–24 mm Hg) in 9084 (22·7%) of 40 082 patients

Discussion

To our knowledge, these data provide the first evidence-based information on the continuum of clinical risk related to PVR in patients with elevated pulmonary artery pressure. Specifically, our findings show that PVR of 2·2 Wood units or more is associated with a sizeable increase in adjusted mortality risk, which was consistent across two RHC referral cohorts and particularly evident in the absence of frank postcapillary pulmonary hypertension (ie, PAWP >15 mm Hg). Results from this study,

Data sharing

The data from the primary cohort that support the findings of this study are available from the corresponding author on reasonable request, although they will be subject to the stringent data privacy rules of the Veterans Affairs Healthcare System and the US government. The data from the validation cohort that support the findings of this study are available from ELB at Vanderbilt on reasonable request, although they will be subject to the stringent data privacy rules of Vanderbilt's BioVU

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