literature review pulmonary hypertension

• Research article
• Open access
• Published: 28 July 2020

Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal

• Max Schlueter   ORCID: orcid.org/0000-0003-1772-1421 1 ,
• Amélie Beaudet 2 ,
• Evan Davies 2 ,
• Binu Gurung 1 &
• Andreas Karabis 3 , 4  

BMC Pulmonary Medicine volume  20 , Article number:  202 ( 2020 ) Cite this article

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Metrics details

The clinical landscape of pulmonary arterial hypertension (PAH) has evolved in terms of disease definition and classification, trial designs, available therapies and treatment strategies as well as clinical guidelines. This study critically appraises published evidence synthesis studies, i.e. meta-analyses (MA) and network-meta-analyses (NMA), to better understand their quality, validity and discuss the impact of the findings from these studies on current decision-making in PAH.

A systematic literature review to identify MA/NMA studies considering approved and available therapies for treatment of PAH was conducted. Embase, Medline and the Cochrane’s Database of Systematic Reviews were searched from database inception to April 22, 2020, supplemented by searches in health technology assessment websites. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist covering six domains (relevance, credibility, analysis, reporting quality and transparency, interpretation and conflict of interest) was selected for appraisal of the included MA/NMA studies.

Fifty-two full publications (36 MAs, 15 NMAs, and 1 MA/NMA) in PAH met the inclusion criteria. The majority of studies were of low quality, with none of the studies being scored as ‘strong’ across all checklist domains. Key limitations included the lack of a clearly defined, relevant decision problem, shortcomings in assessing and addressing between-study heterogeneity, and an incomplete or misleading interpretation of results.

Conclusions

This is the first critical appraisal of published MA/NMA studies in PAH, suggesting low quality and validity of published evidence synthesis studies in this therapeutic area. Besides the need for direct treatment comparisons assessed in long-term randomized controlled trials, future efforts in evidence synthesis in PAH should improve analysis quality and scrutiny in order to meaningfully address challenges arising from an evolving therapeutic landscape.

Peer Review reports

Pulmonary arterial hypertension (PAH) is a rare and debilitating chronic disease of the pulmonary vasculature [ 1 ]. Disease progression is characterized by increasing pulmonary vascular resistance (PVR) and non-specific symptoms (e.g., dyspnoea during exercise, fatigue, chest pain, and light-headedness), that ultimately leads to right heart failure and premature death [ 1 , 2 ]. Prior to the availability of PAH-specific therapies, median survival time was documented as 2.8 years in the US patients with PAH [ 3 ]. Five-year survival rate in newly diagnosed patients is reported to be 61.2% [ 4 ].

Therapies in PAH have been approved with one or more routes of administration for three key pathogenesis pathways. Approved therapies targeting the nitric oxide pathway are the phosphodiesterase-5 inhibitors (PDE-5I): sildenafil (oral or intravenous [IV]) and tadalafil (oral), and the soluble guanylate cyclase stimulator (sGCS) riociguat (oral). Therapies targeting the endothelin pathway currently approved are macitentan, bosentan and ambrisentan, all administered orally. One of the endothelin receptor antagonist (ERA) drugs, sitaxentan, was authorised in Europe in 2006, but subsequently withdrawn due to liver toxicity [ 5 ]. Approved drugs targeting the prostacyclin [PGI2] pathway include epoprostenol (IV), iloprost (inhaled), treprostinil (IV, inhaled, oral, subcutaneous [SC]), beraprost (oral), and selexipag (oral), a selective non-prostanoid PGI2 receptor (IP receptor) agonist.

The treatment of PAH is guided by an evidence-based treatment algorithm published by the European Society of Cardiology and European Respiratory Society (ESC/ERS) [ 2 ]. The overall treatment goal is to achieve a low-risk status, associated with World Health Organization (WHO) Functional Class II, and good exercise capacity (> 440 m in the 6-min walking distance test), and right-ventricular function assessed using echocardiography. The latest guidance and proceedings (see Figure S 1 in the electronic supplementary material) recommend either monotherapy or initial oral combination therapy for treatment-naïve patients at a low or intermediate risk of clinical worsening or death [ 2 , 6 ]. For these patients, oral therapies are recommended, therefore ERA and PDE-5I are generally used as first-line treatment. For patients who fail to achieve an adequate clinical response (i.e. a low-risk status after 3 to 6 months) with initial therapy, treatment with sequential double or triple combination therapy is recommended. For high-risk treatment-naïve patients, an initial combination therapy regimen including a drug targeting the PGI2 pathway requiring continuous IV administration is indicated.

A lack of head-to-head treatment comparisons in randomized controlled trials (RCTs) has compounded clinical decision-making in PAH. As a result, a multitude of meta-analyses (MA; the synthesis of evidence from the same treatment comparisons assessed in clinical trials [ 7 ]) and network meta-analyses (NMA; the synthesis of evidence from both direct and indirect evidence to allow treatment comparisons that have not been directly assessed in clinical trials [ 7 ]) in PAH have been conducted.

Given the absence of direct RCT comparisons and the evolution of disease definition, classification, trials designs, available therapies and treatment guidelines, it is important to better understand the quality of published MA and NMA in PAH and their alignment with clinical decision-making today. The objective of the study was to critically appraise the quality and validity of published MA and NMA studies in PAH and explore the impact of the findings from these studies on current decision-making.

Search strategy and data collection

A systematic literature review was conducted according to the recommendations of the Cochrane Collaboration [ 8 ] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 9 ], to identify published evidence synthesis (i.e. MA and NMA) studies in PAH.

Searches were conducted from the database inception to September 12, 2018 and updated on April 22, 2020 in Embase, Medline (including Medline-In-Process) and the Cochrane’s Database of Systematic Reviews via OVID in line with The National Institute for Health and Care Excellence (NICE) technology appraisal guidelines and recommendation from Centre for Review and Dissemination and the Cochrane Collaboration [ 10 , 11 , 12 ]. Supplementary searches included websites of selected health technology assessment agencies.

Retrieved records were assessed by one reviewer against the pre-specified PICOS criteria (Table S 1 in the electronic supplementary material) and unblinded assessments were double checked by the second reviewer. Any discrepancies were resolved through discussion with a third reviewer. Studies were included if they met the following criteria: 1) adult patients with any etiology of PAH (pulmonary hypertension (PH) Group 1) [ 2 ], 2) at least two approved and available therapies or drug classes for treatment of PAH (to allow assessment of relative efficacy and safety of compared treatments), 3) full-text MA/NMA report. Details of the search methodology are provided in Tables S 2 a-h in the electronic supplementary material.

Key baseline characteristics of patients with PAH from the included RCTs were extracted to explore the extent of heterogeneity across the trials.

Study appraisal

A targeted review of published checklists for evidence synthesis studies was conducted. Checklists published by NICE [ 13 ], ISPOR [ 14 ], PRISMA [ 15 ] and GRADE [ 16 ] were identified. Criteria for checklist selection included:

Domains covered, such as relevance of research question, methods for establishing the evidence base, assessment for internal validity, statistical methods, and reporting of results

Suitability to present context, including applicability to different forms of evidence synthesis

Generalizability

Acceptability and recognition of the checklist

The ISPOR checklist was deemed the most appropriate as it covers all domains listed in the checklist selection criteria, is suited to the study objective and is applicable to different types of evidence synthesis.

Complementary questions were added to the 26-item ISPOR checklist with questions specific to the disease area and/or study objective. These additional questions are marked as such in the study assessment provided in Table S 3 in the electronic supplementary material.

The ISPOR checklist provides for a quality grading whereby an overall assessment of ‘strong’, ‘neutral’ or ‘weak’ is given for each of the six domains (i.e. relevance, credibility, analysis, reporting quality & transparency, interpretation, conflict of interest). However, no explicit criteria are provided for scoring each domain. A set of criteria specific to each domain for quality grading was therefore adopted which is described in Table 1 . Study appraisals by one reviewer were double checked by a second reviewer.

Study characteristics

A total of 52 MA and NMA studies met the inclusion criteria and were retained for data extraction and quality appraisal. From electronic database searches, 51 full-text publications were included. From the hand-search of publicly available websites of health technology assessment bodies, one report of the Canadian Agency for Drugs and Technologies in Health was included. The PRISMA diagram in Figure S 2 a-b (see electronic supplementary material) presents the search results.

The study characteristics of 52 publications included for appraisal are presented in Table  2 . The publication year ranged between 2007 [ 44 ] and 2020 [ 39 , 41 , 49 , 50 ] with most studies published in recent years. MAs were conducted in 35 studies [ 17 , 19 , 20 , 22 , 23 , 26 , 27 , 28 , 29 , 31 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 44 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 55 , 58 , 60 , 61 , 62 , 65 , 66 , 67 , 68 , 69 ], NMAs in 15 studies [ 18 , 21 , 24 , 25 , 30 , 32 , 33 , 42 , 49 , 50 , 54 , 56 , 59 , 63 , 64 ], both NMA and MA in one study [ 57 ], and MA and disproportionality analysis in one study [ 34 ]. Of 52 studies, 47 evaluated the impact of PAH interventions in patients with PAH and PAH subgroups (based on aetiology, e.g. idiopathic PAH, familial PAH, connective tissue disease-associated PAH). Patients with PH including PAH and non-PAH patients (e.g. PH due to left sided heart disease) were investigated in four studies [ 20 , 34 , 44 , 45 ] while patients with PAH were examined alongside other diseases (e.g. heart failure, prostate cancer) in two studies [ 46 , 60 ].

Baseline characteristics of patient populations in the included studies are presented in Fig. 1 a-c. The average WHO Functional Class distribution, a measure of disease severity, was 0.6, 30.3, 63.7 and 5.4% for FC I, FC II, FC III and FC IV, respectively.

a-c Disease severity, PAH etiology and background therapy across included RCTs

With a number of exceptions [ 17 , 20 , 24 , 25 , 34 , 35 , 39 , 40 , 41 , 46 , 48 , 56 , 60 , 61 , 63 , 64 , 66 ], most studies investigated treatments targeting all three pathways. All the approved treatments (ERA, PDE-5Is, PRAs, prostacyclin and sGCS) were investigated in nine recent studies [ 27 , 30 , 38 , 42 , 47 , 49 , 50 , 59 , 65 ]. Some studies included treatments approved in limited markets such as beraprost [ 38 , 40 , 49 , 50 , 52 , 53 , 59 , 63 , 67 ]. In nine studies, drugs targeting one pathway only were investigated: prostacyclins in five studies [ 40 , 48 , 61 , 63 , 66 ] and ERAs in four studies [ 25 , 46 , 60 , 64 ]. Fifteen studies [ 17 , 20 , 21 , 24 , 25 , 32 , 34 , 35 , 39 , 46 , 60 , 62 , 64 , 65 , 67 ] focused on oral treatments only. Besides the approved treatments, non-approved PAH treatments were included in seven studies: imatinib [ 52 , 53 , 56 , 62 ], terbogrel [ 29 , 62 ] and aspirin [ 52 ]. Despite being withdrawn in 2010, sitaxentan was assessed in four recent studies [ 25 , 35 , 59 , 62 ]. Two studies omitted selexipag despite being approved at the time of study [ 30 , 54 ].

The outcomes evaluated included clinical, hemodynamics, health-related-quality-of -life (HRQoL) and safety. Frequently investigated clinical endpoints were 6MWD (as a standalone or within combined events) in 43 studies [ 17 , 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 39 , 40 , 41 , 42 , 44 , 45 , 47 , 48 , 49 , 50 , 51 , 52 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 65 , 66 , 67 , 68 ] followed by mortality (all-cause or disease-specific) in 37 studies [ 18 , 19 , 20 , 21 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 33 , 37 , 40 , 41 , 42 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 57 , 60 , 61 , 62 , 63 , 65 , 66 , 67 , 68 ], clinical worsening (standalone or in combined events) in 25 studies [ 18 , 19 , 20 , 21 , 24 , 25 , 26 , 27 , 30 , 31 , 33 , 35 , 37 , 38 , 42 , 47 , 54 , 57 , 59 , 61 , 62 , 65 , 66 , 67 , 68 ] and WHO functional class improvement or deterioration in 24 studies [ 18 , 19 , 20 , 24 , 27 , 29 , 31 , 32 , 33 , 35 , 37 , 40 , 42 , 44 , 45 , 47 , 48 , 55 , 57 , 59 , 60 , 63 , 65 , 67 ].

The most commonly employed tool for quality assessment was Cochrane’s risk of bias tool, employed in 21 studies [ 20 , 21 , 27 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 41 , 47 , 48 , 49 , 51 , 60 , 62 , 64 ] followed by Jadad scores used in 12 studies [ 17 , 25 , 26 , 30 , 40 , 42 , 48 , 51 , 61 , 65 , 66 , 67 ]. There was no mention of quality appraisal being conducted in 10 studies [ 18 , 24 , 28 , 29 , 44 , 45 , 55 , 58 , 63 , 64 ].

• Quality appraisal

The quality assessment of the included studies is summarized in Fig.  2 by overall judgement (strength, neutral, weakness) against each domain of the checklist and the number of studies scoring each judgement in each domain in Table  3 . The detailed quality assessments are presented in Table S 3 in the electronic supplementary material.

Overview of quality assessment

Of the 52 studies reviewed, eight were scored as strong in terms of relevance, 26 as neutral, and the remaining 18 as weak.

Most included studies included relevant populations. In some cases, the population was narrowly defined and thus not generalizable to an overall PAH population (e.g. focused on connective tissue disease-associated-PAH [ 36 , 39 ]) while in others, it went beyond adult PAH populations (i.e. PH patients [group 2–5] or pediatric PAH were included). Some studies adopted a narrow research focus on 1–2 drug classes [ 17 , 20 , 25 , 32 , 35 , 39 , 40 , 60 , 61 , 63 , 64 , 66 ] or oral therapies only [ 17 , 20 , 21 , 32 , 35 , 39 , 62 , 64 , 65 , 67 ], often without explicit and/or adequate justification for such restrictions. Many included studies were highly selective in their choice of outcomes analyzed, 6MWD being the most frequently analyzed outcome.

Very few studies fulfilled the checklist item about the extent to which an evidence synthesis study is informative to decision makers today and aligned with the current clinical practice and guidelines. Several papers did not explicitly state the research question or decision problem guiding the analysis [ 18 , 21 , 29 , 33 , 42 , 55 , 61 ]. Several other studies failed to justify the focus or their research question [ 17 , 18 , 20 , 21 , 25 , 31 , 32 , 40 , 45 , 60 , 62 , 63 , 64 , 65 , 66 ]. For example, some studies formulated research questions with a very narrow scope (e.g. oral treatments [ 17 , 20 , 21 , 32 , 62 , 64 , 65 ]) or included trials with non-PAH populations [ 34 , 44 , 45 ], therefore precluding determination of the optimal choice of therapy based on a comparison of all available treatment options. Some studies included unapproved or withdrawn treatments, while several studies made conclusions at odds with current knowledge, guidelines and clinical practice. For example, claims of PDE-5I monotherapy being superior and a therapy of choice based on older, short-term trials (e.g. Singh 2006 [ 70 ], Galie 2005a [ 71 ]) are not aligned with evidence from more recent, longer-term studies suggesting that PDE-5I monotherapy is inferior to combination therapy (e.g. SERAPHIN [ 72 ], AMBITION [ 73 ], GRIPHON [ 74 ]). Such inconsistencies across studies challenge a robust interpretation of results for decision makers concerned with a comprehensive assessment of all approved treatments, given the dearth of direct comparisons in RCTs.

Credibility

Of the 52 studies reviewed, six were scored as strong in terms of credibility, 18 as neutral, and the remaining 28 as weak.

The majority of studies attempted to identify all relevant RCTs. Some studies did not search all of the most relevant databases, i.e. MEDLINE, Embase, CENTRAL [ 18 , 29 , 32 , 34 , 35 , 44 , 45 , 52 , 53 , 68 ]. Several studies did not provide details of the search strategy [ 18 , 19 , 20 , 21 , 24 , 25 , 26 , 29 , 31 , 32 , 35 , 36 , 39 , 40 , 44 , 45 , 46 , 49 , 50 , 52 , 53 , 54 , 55 , 59 , 60 , 61 , 63 , 67 , 68 ] and one study did not provide any details on the search strategy and searched databases [ 58 ].

The proposed methodology was found to be relevant to answer the decision problem in almost all included studies. Some studies did not conduct a quality assessment of included RCTs [ 18 , 24 , 28 , 44 , 55 , 58 , 59 ]. Several studies did not provide the results of the RCT quality assessment or discuss implications for the analysis in case of poor quality RCTs [ 21 , 23 , 30 , 31 , 36 , 39 , 46 , 62 , 63 , 68 ].

Given the absence of randomization across the RCTs included in an MA or NMA, the assessment of effect modifiers is essential to validate assumptions around homogeneity, consistency and transitivity [ 75 , 76 ]. Effect modifiers are study and patient characteristics associated with treatment effects, capable of modifying (positively or negatively) the observed effect of a risk factor on disease status. Potential effect modifiers in PAH include patient baseline characteristics such as 6MWD, WHO functional class, disease duration, background therapies and etiology; and study design characteristics such as study duration and imputation rules. As the overview of design and patient baseline characteristics of included PAH RCTs (see Fig. 1 a-c; Figure S 3 a-d in the electronic supplementary material) demonstrates, substantial between-study heterogeneity is a feature of every evidence synthesis study in PAH. The majority of studies did not offer a comprehensive assessment prior to analysis or identify imbalances in effect modifiers across the RCTs [ 17 , 18 , 20 , 21 , 23 , 24 , 25 , 26 , 27 , 30 , 32 , 34 , 39 , 44 , 45 , 46 , 47 , 49 , 51 , 53 , 54 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 68 , 69 ].

Of the 52 studies reviewed, five were scored as strong in terms of analysis, 20 as neutral, and the remaining 27 as weak.

Preservation of study randomization of included RCTs was fulfilled by almost all included studies except in five studies with single-arm [ 36 , 39 , 56 ], retrospective comparative [ 35 ] or open-label extension design [ 58 ]. Several MAs adopted an approach whereby, for multi-arm trials, the control group was split and the sample size halved [ 34 , 37 , 60 , 67 ]. Though outlined in the Cochrane Handbook for Systematic Reviews of Interventions [ 12 ], this approach effectively breaks randomization and should therefore be avoided. Other forms of evidence synthesis (e.g. NMA) are more appropriate in this case. Of the included NMA studies with closed loops, most assessed the consistency between the direct and indirect evidence [ 13 , 14 , 50 , 59 , 64 ].

Common types of analysis to address imbalance in the distribution of treatment effect modifiers include subgroup and sensitivity analysis, meta-regression and using individual patient data. Only about a third of included studies attempted to address between-study heterogeneity [ 22 , 24 , 33 , 35 , 37 , 38 , 40 , 44 , 48 , 50 , 51 , 52 , 53 , 56 , 57 , 61 ]. The majority of included studies (primarily MAs) used a fixed effects model unless marked heterogeneity was detected (typically assessed using the Cochran Q-test or I 2 statistic), in which case a random effects model was used [ 17 , 20 , 25 , 29 , 31 , 34 , 39 , 44 , 45 , 48 , 51 , 59 , 60 , 62 , 65 , 66 , 67 ]. Some studies only fitted a random effects model [ 19 , 20 , 23 , 26 , 27 , 35 , 40 , 46 , 47 , 49 , 50 , 64 ], whereas others only fitted a fixed effects model [ 28 , 30 , 38 ]. The deviance information criterion commonly formed the sole criterion for assessing model fit in the included NMA studies [ 18 , 21 , 32 ] except for Tran et al. 2015 [ 57 ], Petrovic 2020a [ 48 ] and Petrovic 2020b [ 49 ] who assessed model fit based on deviance information criterion and a comparison of the residual deviance with the number of unconstrained data points.

Lastly, several studies pooled treatments at the class level, usually without sound justification for the assumption of a class effect. Very few studies refrained from lumping treatments, doses and co-treatments together [ 28 , 48 , 50 , 55 , 56 , 57 , 62 , 64 ].

Reporting quality & transparency

Of the 52 studies reviewed, seven were scored as strong in terms of their reporting quality and transparency, 22 as neutral, and the remaining 23 as weak.

All included NMA studies presented a network diagram, except Zhang et al. 2016 [ 63 ]. Two of the 11 included NMA studies did not present details of the number and/or RCTs per pairwise comparison [ 18 , 30 ]. Separate reporting of direct and indirect comparisons was omitted in six NMA studies [ 18 , 25 , 30 , 49 , 50 , 56 ]. A ranking of interventions according to the reported treatment effects was provided by two-third of the included NMA studies [ 18 , 25 , 33 , 42 , 49 , 50 , 57 , 59 , 63 , 64 ], some of which did not report associated uncertainty measures. The reporting of all pairwise contrasts between interventions, along with measures of uncertainty, was not adhered by two of the 11 NMA studies [ 18 , 56 ].

The reporting of individual study results was omitted or not fully reported by 14 of the 52 studies [ 21 , 25 , 30 , 32 , 38 , 42 , 46 , 49 , 50 , 55 , 57 , 59 , 63 , 64 ]. Overall, 37 of the included studies either completely omitted a discussion or provided a very brief reference to heterogeneity across studies without a specific discussion of the potential impact of differences in patient characteristics on observed results [ 17 , 18 , 19 , 20 , 21 , 23 , 24 , 25 , 26 , 27 , 29 , 30 , 31 , 32 , 34 , 35 , 36 , 38 , 39 , 46 , 47 , 49 , 51 , 52 , 54 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 67 , 68 ].

Interpretation

Overall, 15 of the 52 studies reviewed were scored as strong in terms of their interpretation of study findings, 23 as neutral, and the remaining 14 as weak.

A number of studies were scored as ‘weak’ when authors did not contextualize results considering limitations [ 31 , 34 , 38 , 39 , 58 , 63 ], or endorsed specific treatments over others without any discussion of between-study heterogeneity and/or despite pooling of active therapies [ 20 , 21 , 25 , 33 , 39 , 59 , 60 ]. For example, Jain et al. 2017 [ 33 ] combined trials [ 74 , 77 , 78 ] in their primary analysis that differed in patients’ severity level and provision of background therapies.

Conflict of interest

Among included studies, 22 were scored as strong in terms of conflict of interest,16 as neutral, and the remaining 14 as weak.

Less than a third of all assessed studies provided either no information about conflicts of interest or insufficiently detailed author disclosures. Other studies reported no personal or financial relationships, or clearly stated author contributions in case of personal or final relationships of affiliations that could have biased the respective study.

The objective of this study was to systematically appraise all identified MA/NMA studies in PAH and assess their quality given that such studies are taken into consideration for evidence-based decision-making. To our knowledge, this is the first study of this type in PAH. Overall, the appraisal found most evidence synthesis studies to be of low quality.

Most included evidence syntheses were found not to have defined the decision problem (i.e. the research question underpinning a study), population, selection of comparisons and outcome selection that is compatible or aligned with current clinical practice and treatment guidelines [ 2 , 79 ]. Of note, the majority of the studies [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 29 , 30 , 32 , 34 , 36 , 40 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 54 , 55 , 57 , 58 , 59 , 60 , 62 , 63 , 64 , 65 , 66 , 68 ] included trials that do not reflect today’s clinical practice. For example, the BREATHE-2 [ 80 ] and PACES [ 81 ] trials investigated bosentan and sildenafil, respectively, as add-on therapy to IV epoprostenol. By contrast, PAH management today typically involves treatment initiation of oral therapy with an ERA and/or PDE-5I in low or intermediate-risk patients comprising the vast majority of patients, whereas parenteral prostacyclins would only be considered or added for high-risk patients [ 6 ].

Notably, clinical trial design has evolved from a preponderance of small, short-term and often open-label studies in treatment-naïve patients with severe PAH to larger, longer-term and event-driven trials (such as COMPASS-2 [ 82 ], SERAPHIN [ 72 ], AMBITION [ 73 ], GRIPHON [ 74 ]) in largely treatment-experienced and less severe patient populations. Similarly, primary endpoint definition has gradually shifted from improvement in 6MWD to morbidity and mortality as a composite endpoint (with components such as all-cause death, PAH-related hospitalization or disease worsening) which is considered to be a more patient- and clinically relevant endpoint [ 83 , 84 , 85 ].

While these changes in trial design and PAH management pose challenges for studies synthesizing evidence generated across such large time spans, a transparent interpretation of findings in recent MA/NMA studies in relation to present clinical practice and guidance was found to be lacking.

A related shortcoming of appraised studies is the choice of outcomes analyzed, which was found to be selective, incomprehensive, and usually not accompanied by clear justification. The most commonly assessed outcome was 6MWD – despite failure of multiple studies to consistently establish significant associations between 6MWD and clinically more relevant outcomes such PAH-related hospitalization, lung transplantation, initiation of rescue therapy or death [ 28 , 29 , 44 , 52 , 86 , 87 ]. Moreover, the assessed evidence synthesis studies generally neither presented a review of the outcome definitions and outcome measures of included trials, nor an assessment of imputation rules for handling missing data.

Mortality was less commonly assessed, which reflects the inherent challenges in designing clinical trials of PAH therapies to detect statistically significant or clinically meaningful differences in mortality. Replication of earlier trials (e.g. Barst 1996 [ 78 ]) showing survival benefit over a very short time period and placebo-controlled RCTs comparing monotherapy with no therapy in treatment-naïve patients would be considered unethical today.

Another crucial drawback in most included studies is the lack of a thorough assessment of key effect modifiers prior to the analysis. As the graphs presenting patient baseline characteristics across PAH trials demonstrate (see Fig. 1 a-c; Figure S 3 a-d in the electronic supplementary material), there is marked between-study heterogeneity. One recurring observation was that most evidence synthesis studies included a mix of PAH and non-PAH patients populations, as in the aerosolized iloprost randomized (AIR) study [ 88 ] which included PAH and chronic thromboembolic pulmonary hypertension (CTEPH) patients.

Only a handful of studies sought to address such potential systematic differences in the effect modifiers through means of subgroup/sensitivity analyses, meta-regression. This may be due to limited subgroup data available from published PAH RCTs, and challenges around smaller sample sizes associated with subgroup data which results in wider uncertainty estimates and lower likelihood of detecting significant relative treatment effects.

In terms of results synthesis, several studies were found to pool treatments at the drug class level. Best practices guidelines in evidence synthesis, such as NICE DSU TSD 7 [ 13 ], recommend against pooling treatment doses or treatments into drug classes since characteristics of the underlying trial population or efficacy/safety trial results may be different.

This review has some limitations. A thorough assessment of the quality of MA/NMA studies is limited by the heterogeneity across included trials. A detailed assessment of between-study heterogeneity in each included MA/NMA was beyond the scope of the review. Nevertheless, a preliminary assessment of patients’ baseline characteristics of all PAH trials included across the appraised MA/NMA studies was considered reflective of most studies. Results or analyses relating to PAH subgroups by etiology, severity or age were not explored further due to no or very limited studies focusing on these specific sub-populations.

This is the first critical appraisal of published MA/NMA studies in PAH, suggesting overall low quality and validity of efforts synthesizing PAH evidence. As our study demonstrates, this has important implications for clinical decision-making and future research. First, the choice of optimal therapy to maximize patient outcomes should also be guided by a consideration of the limitations of published MA/NMA studies highlighted in this study. Second, future attempts of evidence synthesis in PAH should improve the level of validity and scrutiny to meaningfully address challenges arising from an evolving therapeutic landscape. This should include the definition of decision problems that are aligned with today’s clinical practice and treatment guidelines, justification of key analysis assumptions, a comprehensive interrogation of the evidence base prior to analysis, use of individual patient data to mitigate issues of heterogeneity, and a transparent presentation of results and associated uncertainty measures for all relevant outcomes.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Chronic thromboembolic pulmonary hypertension

Endothelin receptor antagonist

European Respiratory Society

The European Society of Cardiology

Health-related-quality-of -life

International Society for Pharmacoeconomics and Outcomes Research

Intravenous

Meta-analyses

The National Institute for Health and Care Excellence

Network-meta-analyses

Pulmonary arterial hypertension

Phosphodiesterase-5 inhibitors

Participants, interventions, comparisons, outcomes, and study design

Pulmonary Hypertension

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Pulmonary vascular resistance

Randomized controlled trials

Soluble guanylate cyclase stimulator

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The authors thank Dr. Rainer Zimmerman for his review and valuable comments on the manuscript from a clinical perspective.

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Additional file 1: table s1..

Eligibility criteria of the Systematic Literature Review. Table S2a-d. Search strategies (September 2018). Table S2e-h. Search strategies (April 2020 update). Table S3. Quality assessment of included evidence synthesis studies. Figure S1. Treatment algorithm. Figure S2a. PRISMA diagram showing study selection process (September 2018). Figure S2b. PRISMA diagram showing study selection process (April 2020 update). Figure S3a-d. Mean age, gender, disease duration and 6MWD in included RCTs.

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Schlueter, M., Beaudet, A., Davies, E. et al. Evidence synthesis in pulmonary arterial hypertension: a systematic review and critical appraisal. BMC Pulm Med 20 , 202 (2020). https://doi.org/10.1186/s12890-020-01241-4

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Diagnosis and Treatment of Pulmonary Arterial Hypertension : A Review

• 1 Pulmonary, Critical Care, and Sleep Medicine, Tufts Medical Center, Boston, Massachusetts
• 2 Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
• Correction Error in Table JAMA

Importance   Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death.

Observations   Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide–cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide–cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previous conventional single-pathway targeted monotherapy.

Conclusions and Relevance   Pulmonary arterial hypertension affects an estimated 10.6 per 1 million adults in the US and, without treatment, typically progresses to right heart failure and death. First-line therapy with drug combinations that target multiple biological pathways are associated with improved survival.

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Ruopp NF , Cockrill BA. Diagnosis and Treatment of Pulmonary Arterial Hypertension : A Review . JAMA. 2022;327(14):1379–1391. doi:10.1001/jama.2022.4402

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A clinician's guide to pulmonary hypertension

Wilson, Bailey K. MMSc, PA-C; Sadowski, Catherine K. MHS, PA-C; Baeten, Robert G. DMSc, PA-C, FCCP

Bailey K. Wilson practices at Wellstar Colon Rectal in Roswell, Ga. Catherine K. Sadowski is a clinical associate professor in the PA program at Mercer University in Atlanta, Ga. Robert G. Baeten is a clinical assistant professor in the PA program at Mercer University and practices in cardiac critical care at Northside Hospital in Canton, Ga. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Earn AAPA Category 1 CME credit by reading both CME articles in this issue, reviewing the post-test, then taking the online test at http://cme.aapa.org . Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 AAPA Category 1 CME credit. The term of approval is for 1 year from the publication date of April 2024.

Despite advances in diagnosis and treatment, pulmonary hypertension has high morbidity and mortality. The presenting symptoms often are vague and may mimic other more common diseases, so patients can be misdiagnosed or missed early in the disease process. Early detection of pulmonary hypertension by primary care providers can play an important role in patient outcomes and survival. Identifying signs and symptoms, understanding the causes and classifications, and knowing the systematic approach to evaluating and diagnosing patients with suspected pulmonary hypertension are key to preventing premature patient decline.

Pulmonary hypertension is a heterogeneous disease composed of a number of different disorders characterized by abnormally high pressures in the lung vasculature ( Table 1 ). 1 The causes of the abnormally high pressures vary, but the resulting symptomatology is largely the same.

Normal pulmonary arterial systolic pressure is between 15 and 30 mm Hg, and normal pulmonary arterial diastolic pressure ranges from 4 to 12 mm Hg; mean pulmonary arterial pressure (mPAP) values range from 9 to 18 mm Hg. 2 The pulmonary vascular bed normally is low resistance, and can hold a patient's entire cardiac output at pressures 15% to 20% of the systemic circulation. 2

Pulmonary hypertension is defined hemodynamically as an mPAP greater than 20 mm Hg. 3 Abnormally high pressures in the pulmonary vasculature result from pulmonary vessel remodeling or increased downstream pressures. 4 These physiologic changes lead to a decrease in the diffusing capacity of the lungs and, over time, the right ventricle enlarges to adapt to the increase in afterload. 5 As a result, patients typically develop dyspnea, fatigue, exercise intolerance, and, in more advanced disease, symptoms of right-sided heart failure, systemic fluid overload, and eventually death. 3

Most often, pulmonary hypertension is a complication of an underlying cardiovascular or pulmonary disease. Development is associated with worsening symptoms and reduced life expectancy independent of the underlying disease. 6 From 2003 to 2020, about 126,526 people died in the United States from pulmonary hypertension; 66% were women and 34% men. 7 Higher mortality also was observed in Black patients and those living in rural areas. 7

The World Health Organization classifies pulmonary hypertension into five clinical groups: Group 1, pulmonary arterial hypertension (PAH); Group 2, pulmonary hypertension caused by left-sided heart disease (PH-LHD); Group 3, pulmonary hypertension caused by chronic lung disease (PH-CLD); Group 4, chronic thromboembolic pulmonary hypertension (CTE-PH); and Group 5, pulmonary hypertension with unclear and/or multifactorial mechanisms ( Table 1 ). 1 Grouping patients with similar pathologic findings, hemodynamic characteristics, and treatment lets clinicians communicate effectively about the different causes and standardize the diagnostic workup and treatment. 1

Most forms of pulmonary hypertension are managed by treating the underlying disease. However, targeted therapeutic options are available for patients with PAH (Group 1). Surgical management can be an option for patients with PAH refractory to medical treatment and patients in Group 4 (CTE-PH). 2 Without treatment, all forms of pulmonary hypertension cause progressive right heart failure, which often is fatal.

PATHOPHYSIOLOGY AND PREVALENCE

To diagnose and treat pulmonary hypertension appropriately, clinicians must understand the distinctive features of the various clinical classifications in each of the five groups.

• Group 1 . PAH is characterized by precapillary pulmonary hypertension with resting mPAP greater than 20 mm Hg, pulmonary arterial wedge pressure (PAWP) of 15 mm Hg or less, and pulmonary vascular resistance (PVR) greater than 2 Wood units. 1 Environmental and genetic insults are thought to initiate the disease. 8 This process leads to increased PVR. 9

Although PAH is relatively rare, with a prevalence of 5 to 25 cases per 1 million population and an incidence of 2 to 5 cases per 1 million population per year, it has significantly higher morbidity and mortality than other forms of pulmonary hypertension. 10,11 PAH most commonly is idiopathic (50% to 60% of cases). 3 Historically, it was more common in young to middle-aged women without coexisting medical conditions , but now is more frequently diagnosed in patients ages 65 years and older with cardiovascular comorbidities and is diagnosed at about the same rates in men and women. 3,12 Other causes include inherited genetic mutations, connective tissue disease, and drugs or toxins ( Table 1 ). 1 Clinicians can distinguish PAH from other classifications based on hemodynamic information revealed on echocardiogram. 2

• Group 2 . PH-LHD is a form of postcapillary pulmonary hypertension defined by mPAP greater than 20 mm Hg at rest and PAWP greater than 15 mm Hg on right heart catheterization, and is the most common type of pulmonary hypertension. 6 The two hemodynamic phenotypes are isolated postcapillary pulmonary hypertension and combined pre- and postcapillary pulmonary hypertension. 6 Between 65% and 80% of cases of pulmonary hypertension are caused by LHD. 13 Progressive increase in left atrial pressure occurs as a result of heart failure with reduced or preserved ejection fraction or valvular heart disease. 14
• Group 3 . PH-CLD is a form of precapillary pulmonary hypertension with mPAP greater than 20 mm Hg at rest, PAWP of 15 mm Hg or less, and PVR of 3 Wood units or greater on right heart catheterization. 6 Causes include chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and other conditions that cause chronic hypoxia, such as obesity hypoventilation syndrome or overlap syndrome (a combination of obstructive sleep apnea and COPD). 6 Hypoxia induces vasoconstriction in the lungs, redirecting blood flow to areas of higher oxygenation for more effective gas exchange. Chronic hypoxia causes widespread vasoconstriction of the lung vasculature, which over time leads to vascular remodeling; this in turn causes increased PVR. 15

The prevalence of pulmonary hypertension in patients with COPD varies depending on the patient's stage of COPD, the kind of diagnostic tool used, and the definition used for pulmonary hypertension. 15 The key point for clinicians is not to underestimate the likelihood that most patients with COPD will develop pulmonary hypertension. 15 Between 8% and 15% of patients with idiopathic pulmonary fibrosis (IPF) have pulmonary hypertension at initial diagnosis; this figure rises to 30% to 50% of patients with advanced IPF and more than 60% of those with end-stage IPF. 15

• Group 4 . CTE-PH is a form of precapillary pulmonary hypertension with mPAP greater than 20 mm Hg at rest, PAWP of 15 mm Hg or less, and PVR of 3 Wood units or greater on right heart catheterization. 6 Subgroups are based on the underlying cause. This rare form of pulmonary hypertension is caused by increased clotting and persistent thrombi following pulmonary embolisms after at least 3 months of therapeutic anticoagulation. 3 The clots obstruct the pulmonary arteries, causing increased pressure in the lungs and diminished blood flow, leading to hypoxia and pulmonary vascular remodeling. 16 The estimated incidence of CTE-PH is 0.9 patients per million and the estimated prevalence is 14.5 to 144 patients per million adults. 11
• Group 5 . Pulmonary hypertension associated with one of several complex disorders and multiple etiologic factors may be secondary to increased pre- or postcapillary pulmonary hypertension or direct effects on pulmonary vasculature. 6 Precapillary hypertension is characterized by mPAP greater than 20, PAWP of 15 or less, and PVR greater than 2 Wood units; postcapillary hypertension is characterized by mPAP greater than 20, PAWP greater than 15, and PVR less than 2 Wood units. 6 Causes include hematologic disorders, metabolic disorders, chronic renal failure, and complex congenital heart disease. 4 The incidence and prevalence of pulmonary hypertension in most of these disorders is unknown. 3

CLINICAL MANIFESTATIONS

Progressive dyspnea is the most common symptom of pulmonary hypertension, occurring as an initial symptom in more than half of patients and eventually present in about 85%. 2 A high index of suspicion is needed to diagnose pulmonary hypertension; thus, clinicians should consider it in patients with exertional dyspnea. Studies have estimated that 21% of patients experienced a 2-year delay in receiving a diagnosis of pulmonary hypertension after symptoms began. 4 Other symptoms include fatigue, chest pain, presyncope or syncope, lower extremity edema, and palpitations. 2

As the disease progresses, symptoms progress to those of right-sided heart failure, including weight gain from fluid retention, right upper quadrant abdominal pain from hepatic congestion, and other signs of systemic venous congestion.

Poch and Mandel note that physical examination findings may be unremarkable in patients in the early stages of pulmonary hypertension, but as the disease progresses, findings suggestive of pulmonary hypertension include right-sided heart failure and systemic fluid overload. 2 Signs may include jugular venous distension, hepatojugular reflux, hepatomegaly, ascites, peripheral edema, left parasternal heave, and S 3 gallop. Less common symptoms include exertional chest pain, wheezing, cough, atelectasis, and Ortner syndrome ( Figure 1 ). 17

The combination of peripheral edema, right ventricular heave, and elevated jugular venous pressure highly suggests the presence of severely elevated mPAP and requires urgent diagnostic evaluation. 18 Physical examination findings such as crackles, wheezing, heart murmurs, peripheral cyanosis, and other signs of left heart failure are more suggestive of PH-LHD or PH-CLD. 2 When evaluating a patient with similar signs and symptoms, such as patients with left-sided heart failure, valvular heart disease, or obstructive or restrictive lung diseases, clinicians should keep pulmonary hypertension on the differential.

The wide range of underlying disorders and conditions that can lead to pulmonary hypertension can complicate its diagnosis. In patients presenting with symptoms and physical examination findings consistent with pulmonary hypertension, common tests include ECG, chest radiograph, and pulmonary function tests (PFTs). Transthoracic echocardiography also can be useful to estimate the probability of pulmonary hypertension. 19 The role of diagnostic testing is not only to confirm the presence of pulmonary hypertension, but to help identify the underlying cause and classify it. By classifying patients with PAH, CTE-PH, or other forms of severe pulmonary hypertension, clinicians can appropriately refer them to pulmonary hypertension centers for specialized care. 20

In 2022, the European Society of Cardiology (ESC)/the European Respiratory Society (ERS) issued guidelines for the diagnosis and treatment of pulmonary hypertension. 3 If a clinician has a patient with unexplained dyspnea or is suspected of having pulmonary hypertension, the clinician can refer to a diagnostic algorithm to approach the clinical workup ( Figure 2 ). 3 The algorithm has three steps:

Patients are likely to present to their primary care providers (PCPs) with nonspecific cardiovascular or pulmonary symptoms. Perform a comprehensive workup including past medical and family history, physical examination, and bloodwork to narrow the differential diagnosis and point the clinician toward a cardiovascular or pulmonary cause.

Noninvasive cardiac and/or lung testing should be performed next based on the clinician's suspicion of the underlying cause of the symptoms. These tests may include an ECG, chest radiograph, PFTs, arterial blood gas (ABG) analysis, and echocardiogram. Of these tests, the echocardiogram is the most helpful, because it assesses right and left heart morphology and the level of probability of pulmonary hypertension, irrespective of the cause. This information also helps guide subsequent testing for the classification of pulmonary hypertension and determines whether invasive right heart catheterization is warranted. 3

Guidelines recommend using the peak tricuspid regurgitation velocity measured by echocardiography as the key variable for assessing the probability of pulmonary hypertension. 3 However, the presence or absence of pulmonary hypertension cannot be reliably determined by tricuspid regurgitation velocity alone. Peak tricuspid regurgitation velocity is used to separate patients into risk groups: low (2.9 m/s or less), intermediate (greater than 2.9 m/s to 3.4 m/s), and high (greater than 3.4 m/s). 21 Additional echocardiography findings are used to further evaluate a patient's probability of having pulmonary hypertension. Other findings suggestive of pulmonary hypertension include an elevated pulmonary artery systolic pressure, right or left ventricular enlargement, flattening of the interventricular septum, pulmonic insufficiency, midsystolic notching, an enlarged pulmonary artery diameter, and an enlarged inferior vena cava with decreased inspiratory collapse. 16

Confirmation

When echocardiography is highly suggestive of pulmonary hypertension, further diagnostic testing is warranted. Clinicians should focus on ruling out preexisting cardiovascular or pulmonary disease because these are the most common causes of pulmonary hypertension. 6 If the patient has clear echocardiographic findings of LHD (for example, aortic valve disease, mitral valve disease, or heart failure with reduced or preserved ejection fraction in conjunction with evidence of pulmonary hypertension), further testing usually is not required to confirm the diagnosis. 22 If uncertainty remains, consider right and/or left heart catheterization. 14

Patients without evidence of LHD on echocardiography should undergo additional testing to identify noncardiac causes of pulmonary hypertension. 3,13 The most common noncardiac causes of pulmonary hypertension are CLD and CTE-PH. Based on the patient's clinical presentation and reported history, clinicians should order additional testing. In patients with evidence of CLD, echocardiographic findings should be interpreted in conjunction with ABG analysis, PFTs, diffusing capacity of lungs for carbon monoxide, high-resolution chest CT, and a 6-minute walk test. 3 Patients with evidence or history of thromboembolic disease should undergo ventilation-perfusion scanning to evaluate for CTE-PH. 16

After the noninvasive workup has concluded, if the evidence suggests that the patient may indeed have pulmonary hypertension, the gold standard for diagnosis is right heart catheterization. 3 According to Poch and Mandel, right heart catheterization is mandatory to establish a diagnosis of PAH and must be performed before advanced therapies are directed to the pulmonary vasculature. 2

Right heart catheterization provides information on cardiopulmonary hemodynamics, including estimates of pulmonary arterial pressure, right ventricular pressure, and right atrial pressures. A pulmonary capillary wedge pressure (PCWP) of 15 mm Hg or less signifies the absence of pulmonary venous hypertension, which differentiates PAH from other causes of pulmonary hypertension. 3 In addition, a PCWP of 15 mm Hg or greater signifies elevated left atrial pressure from LHD, which is only seen in patients with Group 2 pulmonary hypertension.

Treatment for pulmonary hypertension is based on the underlying pathology, with the 2022 ESC/ERS guidelines as a framework for recommended therapies. 3

TREATING GROUP 1

PAH-specific drug therapies should be prescribed by PAH specialists. PAH treatment involves FDA-approved medications in three major categories: endothelin receptor antagonists, phosphodiesterase (PDE) inhibitors and soluble guanylate cyclase (sGC) stimulators, and prostacyclins. 23,24 These therapies enhance exercise capacity, improve quality of life, and slow disease progression. Each of the therapies, with a goal of lowering pulmonary vascular pressure, carries the risk of common adverse reactions such as systemic arterial hypotension, gastrointestinal (GI) intolerance such as nausea and vomiting related to dilation of the GI vascular bed, headache, and flushing.

What makes these therapies different is that they target unhealthy pulmonary vasculature; traditional vasodilators also affect healthy pulmonary vasculature. 25 Before the development of targeted therapies, patients with PAH had a 1-year survival rate of 69% and a 5-year survival rate of 38%. 26 Since development of targeted therapies over the past 2 decades, the rate for 1-year survival has increased to 85% and for 5-year survival to 57%. 27 Research has borne out that patients who receive treatment within 6 months of diagnosis have a more pronounced effect and better prognosis. 28

However, these therapies are costly and may only be available at certain medical centers. A review by Kaiser Permanente Colorado found that for a patient with PAH, the median total expenditure per day was $56, and 3-year total expenditures were $50,599. 23 Data from the Pulmonary Hypertension Association Registry from 2015 to 2020 found that Black race, public insurance, lower level of education, low household income, higher number of people in household, high body mass index, previous drug use, older age, and male sex are associated with an increased risk of death, hospitalization, and clinical decline. 29 Although targeted therapies offer promise, room for improvement remains in terms of treatment costs and social determinants of health.

Outside of the aforementioned targeted therapies, a subset of Group 1 patients may demonstrate vasoreactivity to oral calcium channel antagonist therapy. The target dosages for patients with PAH are two to three times the dosages typically used for patients with systemic arterial hypertension, which may concern PCPs unfamiliar with this higher dosing. 3

Endothelin receptor antagonists

Bosentan, ambrisentan, and macitentan block the action of endothelin, a peptide that constricts blood vessels. Adverse reactions include peripheral edema and hepatotoxicity. These drugs are teratogenic and should not be used in pregnant patients. 3

PDE inhibitors and sGC stimulators

These therapies are linked to the nitric oxide pathway. Nitric oxide is a signaling molecule that acts as a vasodilator by binding to sGC, which catalyzes the conversion of guanosine triphosphate to cGMP, an intracellular messenger that relaxes smooth muscle. PDE is an enzyme that breaks down cGMP. Sildenafil and tadalafil inhibit the action of PDE-5, promoting vasodilation. Adverse reactions include visual or auditory disturbances. 30 Riociguat stimulates sGC, leading to increased production of cGMP and vasodilation even in the absence of nitric oxide. 30

Riociguat and all of the endothelin receptor antagonists are teratogenic and highly regulated by the FDA. 31 The Risk Evaluation and Mitigation Strategy (REMS) is a required risk management plan determined by the FDA that includes special requirements or certifications for prescribers, dispensing pharmacists, documentation of patient safety monitoring such as laboratory tests, and patient enrollment in a registry. 32 Riociguat, for example, is available to female patients only through a REMS program.

Prostacyclin analogs and receptor agonists

Epoprostenol, treprostinil, and iloprost are prostacyclin analogs and mimic the effects of prostacyclin, a naturally occurring substance that dilates blood vessels and inhibits platelet aggregation. 30 Selexipag, a prostacyclin receptor agonist, selectively activates prostacyclin receptors. 30 Common adverse reactions include headache, jaw pain (especially with treprostinil), flushing, and diarrhea.

Combination therapies

Some patients may receive a combination of the above medications for a more comprehensive approach to managing pulmonary hypertension. However, avoid any combination of PDE inhibitors, sGC stimulators, and nitrates because of the risk for severe hypotension. 3 Patients with PAH also should be immunized against COVID-19, influenza, and Streptococcus pneumoniae . 3

TREATING GROUP 2

Pulmonary hypertension secondary to heart failure should be managed with diuretics. 3 Use of medications approved for PAH in patients from Group 2 may have detrimental effects on gas exchange or hemodynamics and is not recommended. 3 Patients should be immunized against COVID-19, influenza, and S. pneumoniae . 33

TREATING GROUP 3

Patients with pulmonary hypertension caused by lung pathologies and/or hypoxia may benefit from supplemental oxygen, noninvasive ventilation, and pulmonary rehabilitation programs. 3 Use of medications approved for PAH in patients with Group 3 pulmonary hypertension may have detrimental effects on gas exchange or hemodynamics. Inhaled treprostinil has FDA approval for treatment of ILD, but the ESC/ERS guidelines suggest only that its use may be considered without providing a strong recommendation. 3,34 Patients with COPD should be immunized against COVID-19, influenza, and S. pneumoniae . 35

TREATING GROUP 4

Treatment includes a combination of surgical pulmonary endarterectomy, balloon pulmonary angioplasty, and medical therapies. Lifelong therapeutic anticoagulation is recommended. Riociguat is recommended for symptomatic patients with CTE-PH or those with persistent pulmonary hypertension after pulmonary endarterectomy. 3

TREATING GROUP 5

No PAH therapies have demonstrated benefit or are recommended for patients in this group. Therapies are confined to treating the underlying disorder. 3

Despite advances in understanding and treating pulmonary hypertension, the disease continues to be associated with high morbidity and mortality. The prevalence of pulmonary hypertension should make clinicians concerned and interested in identifying these patients. Awareness of the condition by PCPs is important because they may be the first to recognize signs and symptoms, leading to diagnosis and treatment.

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pulmonary hypertension; PAH; chronic thromboembolic hypertension; endothelin receptor antagonists; cGMP/PDE inhibitors; prostacyclins

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Pulmonary Hypertension in COPD: A Case Study and Review of the Literature

Affiliations.

• 1 Department of Pulmonary & Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
• 2 Department of Pulmonary & Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. [email protected].
• PMID: 31382489
• PMCID: PMC6723523
• DOI: 10.3390/medicina55080432

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

Keywords: PH-COPD; chronic obstructive pulmonary disease; pulmonary hypertension.

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Conflict of interest statement

None of the authors disclose any conflicts of interest, either real or perceived.

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Chronic thromboembolic pulmonary hypertension is an uncommon complication of COVID-19: UK national surveillance and observational screening cohort studies

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Summary of the background, methods and results of the study, highlighting the two complementary national datasets. COVID-19: coronavirus disease 2019; PE: pulmonary embolism; CTEPH: chronic thromboembolic pulmonary hypertension; PHOSP-COVID: Post-Hospitalisation COVID-19; D-12: Dyspnea-12; NT-proBNP: N-terminal pro-brain natriuretic peptide. Servier Medical Art material used under CC BY 4.0 licence: https://creativecommons.org/licenses/by/4.0

Background Pulmonary embolism (PE) is a well-recognised complication of coronavirus disease 2019 (COVID-19) infection, and chronic thromboembolic pulmonary disease with and without pulmonary hypertension (CTEPD/CTEPH) are potential life-limiting consequences. At present the burden of CTEPD/CTEPH is unclear and optimal and cost-effective screening strategies yet to be established.

Methods We evaluated the CTEPD/CTEPH referral rate to the UK national multidisciplinary team (MDT) during the 2017–2022 period to establish the national incidence of CTEPD/CTEPH potentially attributable to COVID-19-associated PE with historical comparator years. All individual cases of suspected CTEPH were reviewed by the MDT for evidence of associated COVID-19. In a separate multicentre cohort, the risk of developing CTEPH following hospitalisation with COVID-19 was calculated using simple clinical parameters at a median of 5 months post-hospital discharge according to existing risk scores using symptoms, ECG and N-terminal pro-brain natriuretic peptide.

Results By the second year of the pandemic, CTEPH diagnoses had returned to the pre-pandemic baseline (23.1 versus 27.8 cases per month; p=0.252). Of 334 confirmed CTEPD/CTEPH cases, four (1.2%) patients were identified to have CTEPH potentially associated with COVID-19 PE, and a further three (0.9%) CTEPD without PH. Of 1094 patients (mean age 58 years, 60.4% male) hospitalised with COVID-19 screened across the UK, 11 (1.0%) were at high risk of CTEPH at follow-up, none of whom had a diagnosis of CTEPH made at the national MDT.

Conclusion A priori risk of developing CTEPH following COVID-19-related hospitalisation is low. Simple risk scoring is a potentially effective way of screening patients for further investigation.

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Overall rates of CTEPD/CTEPH following hospitalisation with COVID-19 are low, and simplified screening processes using reported breathlessness scores, ECG and NT-proBNP are feasible and may be of significant value https://bit.ly/4aZEEdK

• Introduction

A relationship between coronavirus disease 2019 (COVID-19) and acute pulmonary embolism (PE) has been observed. This is due to endothelial dysfunction and a pro-coagulant inflammatory state [ 1 ]. The incidence of PE varies considerably by severity of COVID-19, complicating an average of 3.4% of COVID-19-related hospital admissions overall [ 2 ] and up to 26% of COVID-19 patients admitted to intensive care [ 3 ].

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but potentially life-limiting complication of PE characterised by obstructive remodelling of the pulmonary arteries [ 4 ]. Prior to the pandemic, ∼3% of patients who survived a PE later developed CTEPH [ 5 ]. The incidence of symptomatic chronic thromboembolic pulmonary disease (CTEPD) where there is significant physiological and symptomatic disease but without resting PH is not currently known. Early identification and diagnosis of CTEPH allows for timelier referral to specialist centres and introduction of treatment, which may improve or cure disease [ 6 ]. To facilitate this, others have sought to devise strategies to help rule out CTEPH after acute PE based on non-invasive investigations that comprise standard clinical workup [ 7 , 8 ].

The relationship between COVID-19 and CTEPH is not yet understood. It seems logical that a proportion of patients will develop chronic disease, but it is unclear if this is to be expected to conform to the same rates as classical causes of PE/CTEPH [ 9 ]. Our previous retrospective study reported a decrease in the rate of CTEPH referrals during the first 12 months of the pandemic and identified no cases secondary to COVID-19 [ 10 ]. This was potentially due to an overburdened healthcare system and a historical median lag time of 14 months from index PE to CTEPH diagnosis [ 4 ]. We have therefore extended this study prospectively to cover the second year of the pandemic. The UK uniquely captures every specialist referral for CTEPD/CTEPH for the whole country because of the nature of the national centrally commissioned service.

The high burden of patients who have developed COVID-19 and the high rates of residual breathlessness [ 11 ] have presented challenges in defining effective and efficient ways to investigate patients in overburdened healthcare systems. In a separate multicentre cohort we sought to apply existing risk-scoring strategies to patients who have survived COVID-19-related hospitalisation. The aim of this was to estimate the proportion of COVID-19-hospitalised patients deemed to be at high risk of CTEPH who may require further investigation, in order to inform guidelines and rationalise the use of outpatient diagnostics.

Two UK national datasets were interrogated to understand the relationship between COVID-19 and CTEPH.

COVID-19-associated CTEPH

All cases of suspected CTEPH referred to the national multidisciplinary team (MDT) at the Royal Papworth Hospital (Cambridge, UK) following at least 3 months of effective anticoagulation were contemporaneously reviewed as part of routine standard of care during the second year of the pandemic (2021–2022). The focus was on the second year of the pandemic as no cases of CTEPH associated with COVID-19 had previously been identified for 2020–2021 [ 10 ]. All referred patients were assessed by PH physicians, cardiothoracic surgeons, interventional cardiologists and radiologists applying the contemporary CTEPH guidelines [ 4 ]. As the Royal Papworth Hospital is the only UK centre that offers pulmonary endarterectomy or balloon pulmonary angioplasty, quaternary-level referrals are received from across the UK and Ireland. Patients with confirmed CTEPD were divided into one of two groups: CTEPH or CTEPD without PH, as per the 2015 European Society of Cardiology/European Respiratory Society guidelines haemodynamic definitions (mean pulmonary arterial pressure ≥25 mmHg, pulmonary arterial wedge pressure ≤15 mmHg, pulmonary vascular resistance >3 WU) [ 4 ]. The 2015 guidelines adhere most closely to the established evidence base and clinical commissioning. Monthly national CTEPH referral rates over the 3-year aggregate baseline mean (March 2017 to February 2020) were compared to the first (March 2020 to February 2021) and the second years (March 2021 to February 2022) of the pandemic by one-way ANOVA.

Each CTEPH and CTEPD case was reviewed for evidence of associated COVID-19 based on clinical referral data, serology and thoracic radiology. Association of COVID-19/PE/CTEPH was determined by a clear linear temporal relationship of COVID-19 with concurrent or subsequent PE within 3 months, followed by CTEPH with symptoms following this trajectory in a typical manner and in the absence of other CTEPH risk factors [ 12 ]. The likelihood of association was subdivided into “very likely” (concurrent PE or PE within 1 month of COVID-19), “probable” (PE within 3 months of COVID-19) or “unlikely” (PE more than 3 months post-COVID-19). We acknowledge causal association here is challenging and have accordingly been circumspect in ascribing causality. However, the temporality, lack of other risks factors and strong associations of COVID-19 with PE [ 1 ] and PE with CTEPH [ 5 ] make causality highly likely. The independent adjudication panel, comprised of four clinicians, was required to form a unanimous specialist opinion. UK Health Research Authority ethical approval was not deemed a requirement for this study as it comprised analysis of retrospectively acquired existing anonymised clinical data.

Non-invasive assessment of CTEPH risk

As part of the PHOSP-COVID (Post-Hospitalisation COVID-19) study [ 11 ], demographic and clinical information was prospectively collected on adults discharged from hospital in the UK with a diagnosis of COVID-19 across 83 centres between 1 February 2020 and 31 March 2021 (ethics approval: 20/YH/0225). All patients >18 years of age who attended follow-up assessment a median (range) of 5 (2–7) months post-hospital discharge were eligible for inclusion. Descriptive data for the cohort includes deprivation scores, body mass index (BMI), smoking history, comorbidities, COVID-19 severity indices, COVID-19 treatment and duration of hospitalisation.

At follow-up patients were reviewed sequentially by the following assessments: 1) clinically reported breathlessness, defined as a Dyspnea-12 (D-12) score >0 [ 13 ]; 2) ECG evidence of right ventricular pressure overload (rSR′ or rSr′ pattern in lead V1 and/or R:S >1 in lead V1 with R >0.5 mV and/or QRS axis >90°) [ 14 ]; and 3) elevated cardiac biomarkers suggestive of ventricular strain, specifically defined as N-terminal pro-brain natriuretic peptide (NT-proBNP) >80 pg·mL −1 [ 8 , 15 ].

Patients were then stratified into one of four groups denoting prospective risk of CTEPH [ 8 ]: 1) very low risk (D-12 score 0), 2) low risk (D-12 score >0 but no ECG criteria), 3) intermediate risk (D-12 score >0 and ≥1 ECG criteria but normal NT-proBNP) and 4) high risk (D-12 score >0 and ≥1 ECG criteria and elevated NT-proBNP).

All 12-lead ECGs were scanned into a central study repository and were individually read by trained physicians to determine whether the prespecified right ventricular pressure overload criteria were met. 10% of each physician's reads were cross-checked by a second clinician to ensure accuracy.

Statistical analysis

Continuous variables are presented as mean with standard deviation or median (interquartile range) and categorical data as count and/or percentage. Comparisons of parametric continuous data were performed using t-tests and ANOVA, whilst categorical data were compared using the Chi-squared test. Comparisons of non-parametric data were performed using the Mann–Whitney U-test or Kruskal–Wallis calculation for multiple-group testing.

Statistical analysis was performed with R version 4.2.3 ( www.r-project.org ).

CTEPH attributable to COVID-19

The pre-pandemic, year 1 pandemic and year 2 pandemic populations were similar in terms of age and sex ( table 1 ). There was no difference between the mean CTEPH referral rate during the second year of the pandemic compared to the pre-pandemic baseline (23.1 versus 27.8 cases per month; p=0.252) ( table 1 ).

• View inline

Chronic thromboembolic pulmonary hypertension (CTEPH) referral numbers, provenance and demographics for pre-pandemic and pandemic years

383 cases of suspected CTEPH were referred during the second year of the pandemic ( figure 1 ). Nine international cases were excluded and 40 had an alternative diagnosis. Of the remaining 334 cases, 277 had CTEPH ( figure 2 ). Six had a history of COVID-19 not temporally related to their diagnosis of CTEPH. Four patients (1.4% of all confirmed CTEPH cases) were identified to have CTEPH with COVID-19-associated PE without other obvious contributing risk factors. In each case the PE caused typical symptoms, was diagnosed by computed tomography (CT) pulmonary angiogram and treated with ≥3 months of anticoagulation. The adjudicating panel judged the overall likelihood of causation in these cases to be “very likely” in two cases and “probable” in two cases. The diagnosis of first PE was <1 and <3 months following COVID-19, respectively [ 9 ]. There were also three cases (two “very likely” and one “probable”) of CTEPD without PH with COVID-19-associated PE [ 8 ].

Flowchart showing the decision-making process to associate coronavirus disease 2019 (COVID-19) infection with subsequent chronic thromboembolic pulmonary hypertension (CTEPH). MDT: multidisciplinary team; PH: pulmonary hypertension; PE: pulmonary embolism.

Illustration of the proportion of chronic thromboembolic pulmonary disease (CTEPD) referrals potentially related to coronavirus disease 2019 (COVID-19). CTEPH: chronic thromboembolic pulmonary hypertension; PE: pulmonary embolism.

Of these four novel CTEPH cases associated with COVID-19 PE, three were female with a mean age of 52.3 years ( table 2 ). Three of the patients had mild index COVID-19 and one case was moderate, as per the World Health Organization classification [ 16 ]. The time from index COVID-19 episode to CTEPH diagnosis ranged from 5 to 21 months. The radiological distribution of disease was proximal in all four cases, and all four patients have undergone pulmonary endarterectomy surgery. None of these cases were from the prospective observational study (PHOSP-COVID), and in our previous work covering the first year of the pandemic no COVID-associated CTEPH cases were diagnosed [ 9 ].

Baseline characteristics of newly diagnosed chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic pulmonary disease (CTEPD) patients over the study period (March 2021 to February 2022) with and without coronavirus disease 2019 (COVID-19)-associated pulmonary embolism

CTEPH risk evaluation following COVID-19 hospitalisation

Over the study period, 1094 patients across the study sites attended secondary care follow-up a median (range) of 5 (2–7) months post-hospital discharge with COVID-19 as part of the PHOSP-COVID study, and had ECG and clinical data available for review by the study team. The average age of this group was 58 years and 659 (60.4%) were male. The mean± sd duration of hospitalisation was 12.6±16.8 days. 66% of the cohort required supplemental oxygen during their admission, whilst a further 15% had required intensive care support.

On review of clinical variables at 3-month follow-up, 324 patients (29.6%) reported no breathlessness and thus were deemed very low risk of developing CTEPH according to the InShape II criteria [ 8 ]. 719 (65.7%) reported breathlessness (D-12 score >0), but had no ECG features of right ventricular strain, so were deemed low risk. Among the 51 patients who reported breathlessness and demonstrated at least one feature of right ventricular strain on their ECG, 24 (2.2%) had a normal NT-proBNP, so were deemed intermediate risk, whilst 11 (1.0%) had elevated NT-proBNP and thus were classified as high risk of developing PH. The remaining 16 patients did not have NT-proBNP assay results available to view and were accordingly deemed unclassifiable, although they were of at least intermediate risk ( figure 3 ).

Flowchart showing the sequential assessment of patients at 3 months post-hospitalisation with coronavirus disease 2019 by Dyspnea-12 (D-12) score, ECG and N-terminal pro-brain natriuretic peptide (NT-proBNP) to risk stratify into very-low-, low-, intermediate- and high-risk categories. # : ECG criteria: rSR′ or rSr′ pattern in lead V1; and/or R:S >1 in lead V1 with R >0.5 mV; and/or QRS axis >90°.

The demographics of the entire study population, and classified according to risk status, are shown in table 3 . There was no significant difference in age or sex between low- and high-risk groups. Patients classified as high risk for developing CTEPH had significantly longer mean± sd inpatient hospital admission (40±45 days for high risk versus 12±16, 13±16 and 15±16 days for very low, low and intermediate risk, respectively; p<0.001).

Data table of all participants in the study and by risk stratification (very low, low, intermediate or high risk) including demographics, comorbidities and descriptive data of the index coronavirus disease 2019 admission

We observe that only a very small proportion of new CTEPH diagnoses are likely to be attributable to COVID-19-associated PE, and also that very few patients hospitalised with COVID-19 are high risk for developing CTEPH at follow-up. This is despite national UK CTEPH referrals returning to pre-pandemic baseline rates. In a separate multicentre cohort we demonstrate that a simple screening algorithm can be applied to determine patients who may need further evaluation.

Our data agree with de J ong et al . [ 17 ], who screened 299 patients who had a diagnosis of COVID-19-associated PE in 13 Dutch hospitals without finding any cases of CTEPH. Our work therefore clarifies that in addition to patients with COVID-19-associated PE having low rates of CTEPH, low rates of referrals have been seen across the whole UK healthcare system, and by applying widely available, cheap clinical tests to patients post-COVID, we can simplify assessment and risk stratification.

As time has elapsed since the onset of the COVID-19 pandemic the knowledge base of long-term sequelae associated with the condition continues to grow. Concurrently, new viral strains continue to appear as COVID-19 evolves and the impact of this is not yet clear. PE has been shown to complicate ∼0.5% of COVID-19 sufferers, an incidence nearly ninefold higher than in those who have not contracted COVID-19 [ 18 ]. Endothelial dysfunction associated with COVID-19 disease gives rise to local inflammation and hypercoagulability, and thrombosis formation that is thought to be predominantly in situ rather than thromboembolic [ 19 , 20 ]. An early case series evaluating necropsy specimens revealed significantly more widespread histological microangiopathy and intussusceptive angiogenesis along with extensive capillary microthrombi in seven patients who died following COVID-19 infection compared to seven necropsy specimens obtained from patients who died of influenza [ 21 ]. It not known for certain, though, whether subsequent viral strains mediate the same pathological effect. PE associated with COVID-19 is significantly less likely to be found in the main pulmonary artery and is more commonly seen in segmental branches when compared to non-COVID-19 patients [ 22 ]. The microscopic, distal nature of pulmonary vascular obstruction in COVID-19 can be difficult to identify with CT or scintigraphy [ 23 ]. It is thus possible that CTEPH may occur in COVID-19 patients without detectable PE, and it is therefore important to have a low index of suspicion to screen for this in symptomatic individuals. Further investigation for the presence of chronic thrombus should be undertaken even when anticoagulated, since delays to CTEPH diagnosis correlate with significantly higher morbidity and mortality, which may be abrogated by prompt initiation of PH-specific treatment [ 4 ]. Our findings suggest that only a small proportion of patients will require screening for CTEPH with more advanced imaging and invasive testing based on existing easily implementable risk calculation [ 8 ].

The low observed prospective risk of CTEPH in hospitalised COVID-19 patients is manifest by the absence of a spike of CTEPH referrals to the national intervention centre during the study period despite the very high incidence of COVID-19 nationally, a crude indicator that there has not been a major influx of CTEPH due to COVID-19 disease. This is not explained by a lower overall rate of referral due to an overburdened healthcare system as we note that the national CTEPH referral rate has rebounded to pre-pandemic levels, reflecting a recovery of referral pathways. The specific incidence of CTEPH after COVID-19 has been sparsely reported in the wider literature. In a small study by C ueto- R obledo et al . [ 24 ], three cases of CTEPH were attributed to COVID-19-associated PE out of 77 total PE diagnoses over an 11-month period. The incidence of 3.8% is comparable to the rate observed in non-COVID-19-associated PE [ 25 , 26 ]. This contrasts with de J ong et al . [ 17 ], whose findings of no CTEPH cases among 299 patients with COVID-19-associated PE derived from multiple Dutch centres more closely mirror our own observed incidence of 1.4%. It is probable that although rare, this emerging disease entity is underdiagnosed given the high incidence of COVID-19-associated PE over the past 2 years. There are many potential explanations for this. Primarily, CTEPH is a rare disease and thus we acknowledge that the issue may just be variance rather than a genuine difference in point estimates of incidence. Mortality bias may be a key contributor as we found COVID-19 patients who were at highest risk of developing CTEPH at 3 months were those with the most severe disease at baseline, requiring longer hospital stay and more advanced treatment, and thus many may not have survived to develop CTEPH. In addition, patients with ongoing symptoms after COVID-19 recovery may have been given alternative diagnoses, including “long COVID”, and as yet there are no structured guidelines for excluding CTEPH. As mentioned, a high index of suspicion is required to investigate for latent CTEPH to avoid omitting or delaying disease-specific treatment, hence the potential value of screening. We await evidence from COVID-19-associated PE cohorts to better define the incidence of, and risk factors for, CTEPH. This may further contribute to our understanding of why we have seen so few cases progress to CTEPH.

None of the current work has yet ascertained CTEPD rates. Research regarding thromboprophylaxis in COVID-19 is also clearly of importance.

Limitations

This national CTEPH dataset is a retrospective analysis, though one that captures a relatively complete dataset from a whole country. The adjudication of whether or not PE, and subsequent CTEPH, was related to COVID-19 in our study was necessarily subjective as no objective criteria are yet established. We also acknowledge that over the subsequent time period more widespread exposure to COVID-19, due to relaxation of quarantine rules, introduction of antiviral therapy and deployment of vaccines, resulted in the virus becoming more “endemic”, making it potentially challenging to establish whether PE was related to COVID-19 infection or spontaneous. We have mitigated this by enforcing strict criteria for the diagnosis of COVID-19-related PE and stipulating that all four clinicians on the independent adjudication panel required unanimous agreement on the diagnosis and limiting the follow-up period to the first 2 years of the pandemic, thus reducing the risk of ascertainment bias. We also note that no change in overall diagnostic rates has been observed, which agrees with the low rates of COVID-19-associated CTEPH seen. Some cases of CTEPH may not have been referred to the national MDT. Finally, the InShape II criteria were not specifically designed for the purpose of risk stratifying the post-COVID-19 patient population.

Conclusions

CTEPD/CTEPH following hospitalisation with COVID-19 remains a differential diagnosis that should be considered in the chronically breathless patient. Our work, however, adds to the literature that suggests that overall rates are not high, and that simplified screening processes using reported breathlessness scores, ECG and NT-proBNP are feasible and may be of significant value.

• Supplementary material

Supplementary Material

Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

Supplementary file: list of members of the PHOSP-COVID Collaborative Group ERJ-01742-2023.Supplement

• Shareable PDF

This one-page PDF can be shared freely online.

Shareable PDF ERJ-01742-2023.Shareable

A list of members of the PHOSP-COVID Study Collaborative Group can be found in the supplementary material .

Ethics statement: UK Health Research Authority ethical approval was not deemed a requirement for this study as it comprised analysis of retrospectively acquired existing anonymised clinical data. PHOSP-COVID ethics approval: 20/YH/0225.

Author contributions: The manuscript was initially drafted by S.A. Reddy and J. Newman, and further developed by the writing committee. J. Newman, S.A. Reddy and M.R. Toshner made substantial contributions to the conception and design of the work and to the acquisition of data. O.C. Leavy made contributions to the analysis or interpretation of data for the work. H. Ghani assisted with data collection. All authors contributed to data interpretation and critical review and revision of the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

This article has an editorial commentary: https://doi.org/10.1183/13993003.01467-2024

Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is Chief Editor of the European Respiratory Journal . The remaining authors have no potential conflicts of interest to disclose.

Support statement: PHOSP-COVID is jointly funded by a grant from the MRC-UK Research and Innovation and the Department of Health and Social Care (DHSC) through the National Institute for Health Research (NIHR) rapid response panel to tackle COVID-19 (grant references: MR/V027859/1 and COV0319). The views expressed in the publication are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the DHSC. Funding information for this article has been deposited with the Crossref Funder Registry .

• Received October 12, 2023.
• Accepted June 9, 2024.
• Copyright ©The authors 2024.

This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.

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Current Respiratory Medicine Reviews

Editor-in-Chief: Joseph Varon School of Medicine The University of Houston Houston TX USA

ISSN (Print): 1573-398X ISSN (Online): 1875-6387

A Literature Review of Pulmonary Arterial Hypertension (PAH)

• Department of Chemistry, Central University of Punjab, Punjab, India

• Department of Chemistry, Banasthali Vidyapith Banasthali-304022, India

Volume 18, Issue 2, 2022

Published on: 29 April, 2022

Page: [104 - 114] Pages: 11

DOI: 10.2174/1573398X18666220217151152

Blood flows from the right side of the heart to the lungs through the pulmonary arteries. Pulmonary arterial pressure refers to the pressure in the arteries of the lungs (PAH). It necessitates immediate treatment because high blood pressure in the lungs causes the right side of the heart to work much harder, increasing the risk of heart failure. This article aimed to provide brief information about the prevalence, pathology, classification, and different therapies of PAH.

Keywords: Pulmonary arterial hypertension (PAH) , Pulmonary capillary wedge pressure (PCWP) , pathology , pathogenesis , endothelin , blood pressure.

Graphical Abstract

Title: A Literature Review of Pulmonary Arterial Hypertension (PAH)

Volume: 18 Issue: 2

Author(s): Ashima Panchal*, Jigar Panchal, Sonika Jain and Jaya Dwivedi

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Panchal Ashima*, Panchal Jigar, Jain Sonika and Dwivedi Jaya, A Literature Review of Pulmonary Arterial Hypertension (PAH), Current Respiratory Medicine Reviews 2022; 18 (2) . https://dx.doi.org/10.2174/1573398X18666220217151152

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Pulmonary Hypertension in COPD: A Case Study and Review of the Literature

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

1. Case Study

A man in his 60s with longstanding chronic obstructive pulmonary disease (COPD) presents himself as a new patient. He has a medical history of New York Heart Association (NYHA) Class I heart failure with a preserved ejection fraction of 60%, hypertension, hyperlipidemia, and a cerebrovascular accident six years ago with no residual deficits. He has smoked a pack of cigarettes a day from the age of 22 until quitting smoking at age 60 when he had a stroke. He indicates that he has been well-controlled on maintenance inhaler therapy, including a long-acting beta-agonist, long-acting muscarinic agent, and inhaled corticosteroid, and has never required oxygen therapy. His ability to perform daily activities is nevertheless somewhat limited by exertional dyspnea. His most recent pulmonary function testing indicates an forced expiratory volume in 1 second (FEV 1 ) of 1.98 L (63% of predicted) and a forced vital capacity (FVC) of 3.24 L (79% of predicted), both values obtained post-bronchodilator, with mildly elevated total lung capacity and residual volume suggesting hyperinflation and air trapping. The diffusion capacity of carbon monoxide on this testing is markedly reduced at 38% of predicted.

He reports a long period during which exacerbations of his COPD were infrequent, with none requiring hospitalization. However, about six months ago, he began to have gradually worsening exercise tolerance for which his inhalers seem to be largely ineffective and he has required two brief hospitalizations for acute exacerbations that were treated with nebulized bronchodilators, corticosteroids, and antibiotics. Concerned about progression of his congestive heart failure, his cardiologist sent him for a repeat transthoracic echocardiogram, which showed no appreciable change in the systolic or diastolic function of the left ventricle but showed new moderate dilation and moderate systolic dysfunction of the right ventricle. Right ventricular systolic pressure could not be measured due to lack of a tricuspid regurgitant jet. Concerned about his progressive symptoms, he presented himself to the outpatient pulmonary practice, where his resting oxygen saturation today is 91%. He has heard some mention of pulmonary hypertension and would like to discuss that topic as it pertains to him.

While the above case is hypothetical, it is typical of our clinical experience and introduces the theme of this review.

2. Discussion and Review of the Literature

2.1. overview, classification, and epidemiology.

Pulmonary hypertension (PH) has traditionally been defined by a mean pulmonary artery pressure of greater than 25 mmHg, though recent work to further classify the disease by the Sixth World Symposium on Pulmonary Hypertension has suggested a lower threshold of 20 mmHg along with pulmonary vascular resistance (PVR) of ≥3 Wood units for pre-capillary disease [ 1 ]. PH exists both as a discrete disease, as in pulmonary arterial hypertension (WHO Group I), or as a disease process attributable to other chronic diseases including chronic cardiac and pulmonary disease.

Efforts to classify pulmonary hypertension in COPD by a 2013 task force proposed to conceptually divide affected patients into two groups: (1) PH-COPD defined in a COPD patient by a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg; and (2) severe PH-COPD, defined by the presence of mPAP ≥ 35 mmHg or ≥ 25 mmHg with the presence of a low cardiac index of <2.0 L/min/m 2 [ 2 ]. The task force suggested that the severe group of patients represented an important minority with disproportionately high rates of vascular remodeling and a loss of circulatory reserve that outpaced the loss of ventilatory reserve. The task force further suggested that this group should be the focus for studies that explore the use of pulmonary vasodilator medications in COPD patients. Indeed, available data suggest that severe PH-COPD represents a phenotype with markedly worsened exercise capacity and prognosis [ 3 ].

Prevalence estimates for PH in patients with COPD are not well-established, as right heart catherization is not routinely performed in this patient population and echocardiography is subject to diagnostic limitations. Estimation is further complicated by the use of a variety of different cutoff values to establish the presence of pulmonary hypertension in prior studies. A 1981 study of 175 patients with moderate-to-severe COPD who underwent right heart catheterization found that 35% had a mean pulmonary artery pressure of >20 mmHg [ 4 ]. At the higher end of estimation, a study of 120 patients with severe emphysema with an average FEV1 of 27% being evaluated for lung volume reduction surgery (LVRS) found that 90.8% of patients had mPAP > 20 mmHg [ 5 ]. Notably, no correlation was found between severity of emphysema and pulmonary artery pressure in this patient group. A study of 998 COPD inpatients admitted for respiratory failure with a mean FEV1 of 33% demonstrated that, while the mean mPAP was 20.3 mmHg, only 2.7% had severe PH, defined as an mPAP ≥ 40 mmHg, with only 1.1% of these patients having only COPD as an attributable cause of PH [ 6 ]. Overall, while elevated mean pulmonary artery pressures appear to be reasonably common in COPD, severe PH out of proportion to underlying lung disease is relatively rare.

2.2. Pathophysiology

In PH secondary to COPD, ongoing chronic hypoxic pulmonary vasoconstriction leads to changes that produce fixed remodeling of the pulmonary vasculature, namely fibromuscular intimal thickening and an increase in smooth muscle of the media of the pulmonary arterioles and arteries [ 7 ]. These same changes have also been noted in the pulmonary vasculature of smokers even without the presence of airflow obstruction [ 8 ]. Increased muscular hyperplasia of the microvasculature and decreases in alveolar capillary density have been found in severe PH-COPD patients, possibly representing a specific subgroup with regard to severity [ 9 ]. Loss of pulmonary vessels, long proposed as an underlying pathological feature of emphysema, may also occur and has been suggested as the key pathophysiological feature of a subtype of PH strongly associated with smoking and low diffusion capacity [ 10 , 11 ]. Increased levels of pulmonary vasoconstrictive mediators including endothelin-1 and decreased expression of endothelial nitric oxide synthase and prostacyclin synthase have also been observed in COPD compared to normal patients [ 12 , 13 , 14 , 15 ]. Genetic determinants also appear to play a role in the differential development of PH in patients with chronic lung disease [ 16 ].

The natural history of PH in COPD may begin with exercise-induced PH that precedes PH at rest. A study of 131 patients with COPD showed that in patients with mild-to-moderate COPD, progression of increases in right-sided pressures was slow, at roughly 0.4 mmHg per year, and that only about 25% of COPD patients with mild-to-moderate hypoxemia were found to have developed resting PH by six years. However, the presence of exercise-induced PH conferred a substantially greater risk of eventually developing resting PH [ 17 ].

These changes as a whole result in increased pulmonary vascular resistance and increased demand on the right ventricle. With progression of disease, the right ventricle may become overtly decompensated, resulting in cor pulmonale.

2.3. Diagnosis

Differentiating symptoms such as dyspnea on exertion or chest tightness as PH from underlying advanced COPD is challenging. The typical physical exam findings of precapillary pulmonary hypertension, such as a loud P2 and/or a holosystolic murmur of tricuspid regurgitation, may be less prominent in COPD patients or more difficult to appreciate due to distant heart sounds on exam. In addition, right heart pressures may not be elevated enough to produce these physical exam findings except during acute exacerbations when pulmonary pressures are demonstrably higher.

Spirometry values have not been shown to reliably correlate with the presence of underlying PH. Significant decrements in diffusion capacity for carbon monoxide (DLCO) may be suggestive of PH, though this is non-specific as this can also be observed in severe emphysema. However, the presence of a disproportionately reduced DLCO with respect to spirometric and radiographic changes of emphysema may be an indication of PH out-of-proportion to underlying COPD that would merit further investigation and treatment [ 6 ].

As discussed above, right heart catheterization, the gold standard for diagnosis of PH, is infrequently performed in patients with COPD unless specific cardiac indications exist, and there are currently no studies demonstrating its clinical usefulness in the routine evaluation of COPD.

Echocardiography represents a useful but limited modality to diagnose PH in the COPD population, with estimation of right ventricular systolic pressure (RSVP) from the velocity of tricuspid regurgitation considered to be a reliable method of detection when this signal is present [ 18 ]. However, in a study of 192 patients with advanced lung disease, including severe COPD, and 50 healthy controls, it was found that tricuspid regurgitation, which is critical for ultrasonographic assessment of PH, could not be assessed in 52% of patients [ 19 ]. In addition, parameters of right heart enlargement and dysfunction alone lacked sufficient specificity to reliably indicate PH in this patient population. Finally, the presence of gas trapping or hyperinflation may limit the echocardiographic technique and prevent accurate estimation of these values, with specificity for detection of PH of only 55% reported in one study of 374 patients with advanced lung disease, of whom over half (68%) had obstructive lung disease [ 20 ].

Imaging modalities such as computed tomography (CT) may offer promise for noninvasive diagnosis of pulmonary hypertension. A study of 60 patients with severe COPD (FEV1 of 27% ± 12%) found a linear correlation between the ratio of pulmonary artery to ascending aorta diameter with mean PA pressure, while such a correlation could not be observed using pulmonary artery systolic pressure (PASP) derived from echocardiography. However, the described area under the curve (AUC) of 0.83 is likely insufficient for truly accurate screening [ 21 ].

2.4. Treatment

Treatment options for COPD-PH remain limited outside of the routine inhaled medications to treat underlying COPD. Long-term oxygen therapy (LTOT) improves survival in COPD patients with hypoxemia and has also been shown to reduce mPAP over a six-month period, presumably by attenuating hypoxic pulmonary vasoconstriction [ 22 ]. However, LTOT does not have proven survival benefits in those with baseline oxygen saturations above the threshold of 89% [ 23 ].

Formal studies of vasodilator therapy in PH-COPD have been largely disappointing, with many demonstrating a measurable improvement in hemodynamics accompanied by worsening hypoxemia due to altered ventilation-perfusion matching, though some trials have shown no net change in oxygenation. Improvements in hemodynamics in these groups do not appear to consistently confer an improvement in symptoms, and some studies have noted worsening exercise tolerance with their use. Trials using pulmonary vasodilators in PH-COPD have also generally been limited by a short trial duration and small numbers of patients, limiting the strength of their conclusions.

Phosphodiesterase-5 inhibitors are often used as first-line therapy in pulmonary arterial hypertension and have been explored by a number of trials in PH-COPD patients. The Sildenafil and Pulmonary HypERtension in COPD (SPHERIC-1) trial was a double-blind, randomized, placebo-controlled trial of 28 patients with PH-COPD (FEV1 of 54% ± 22% in the sildenafil group) that followed patients for 16 weeks on sildenafil 20 mg three times daily [ 24 ]. Significant improvements in hemodynamics, including decreases in mPAP and pulmonary vascular resistance (PVR) and increases in cardiac index, were noted, and no detrimental effects on gas exchange or hypoxemia were found. In addition, BODE index and mMRC score improved, the latter by −0.51 in the experimental group. Notably, this study group had less severe baseline COPD than those typically studied in pulmonary vasodilator trials, with patients with FEV1 < 30% excluded, suggesting that ventilation-perfusion alterations may be subtler and better tolerated in less severe disease. A double-blind and placebo-controlled randomized controlled trial of 10 mg of daily tadalafil in 120 patients with COPD (mean FEV1 of 40%) and PH (measured by RVSP > 30 mmHg on echocardiography) described small improvements in right heart hemodynamics on echo but no improvement in exercise capacity or quality of life. There were no significant differences in SpO2 at the end of the 12-week study [ 25 ].

Endothelin receptor antagonists (ERAs) have also been studied with similar equivocal results. A study by Stolz et al. evaluated the use of bosentan, an endothelin receptor antagonist, in a double-blind randomized trial of 30 patients with severe or very severe COPD [ 26 ]. Of the 20 patients assigned to the bosentan group, six stopped the medication due to adverse side effects prior to the end of the trial. Six-minute walk time actually decreased in the bosentan group, as did mean PaO 2 . Notably, this study was limited by its lack of formal evaluation of the included patients for underlying PH prior to its initiation. A later randomized though not double-blinded trial of 32 COPD patients with confirmed PH (mPAP ≥ 25 mmHg on right heart catheterization) noted improvements in mPAP and PVR in the bosentan group as well as a slight improvement in BODE scores and did not show significant differences in PaO 2 at 18 months, suggesting greater promise for ERAs in a more select group of PH-COPD patients [ 27 ].

Inhaled pulmonary vasodilators have also been studied to a more limited degree in PH-COPD patients. Wang et al. studied the efficacy and safety of inhaled iloprost, a synthetic prostacyclin, in 67 PH-COPD patients, 37 of whom had severe disease by the above criteria and found an average decrease in mPAP of −2.1 mmHg and increase in cardiac output of 0.4 L/min after a single 20 µg nebulized dose without significant changes in PaO 2 or PaCO 2 [ 28 ]. A 2016 study of inhaled treprostinil in a small group of nine PH-COPD patients also found no change in oxygenation based on arterial blood gas but unexpectedly showed decreases in FEV1, FVC, and DLCO [ 29 ].

Real-world use of pulmonary vasodilator medications in PH-COPD has also met with mixed results. Of the 101 patients included in the ASPIRE registry, 43 patients with severe PH-COPD were treated compassionately, mostly with PDE-5 inhibitors, for a duration of at least three months. Survival among these patients was only 72% at one year, not significantly different from the 16 untreated patients despite the treatment group having significantly worse baseline hemodynamics. Of these 43 patients, eight of them showed evident clinical improvement and did show an improvement in survival, suggesting as yet undetermined factors in their disease that rendered vasodilator therapy more beneficial [ 3 ]. Of particular interest, the study did not note significant perturbations in oxygen saturation in patients on vasodilator therapy, though the authors caution that the study was not designed to assess this.

2.5. Prognosis

The negative prognostic implications of an elevated mean pulmonary artery pressure in COPD are well-understood. A 1981 study by Weitzenblum et al. of 175 patients with moderate-to-severe COPD found that survival rates were markedly lower in those that had mPAP above 20 mmHg at four and seven year follow-up, with survival rates at four years of 71.8% in those with mPAP < 20 mmHg and 49.4% in those above 20 mmHg [ 4 ]. In this study, mPAP was as strong a factor for predicting survival as PaO 2 , PaCO 2 , and FEV1. More recently, the ASPIRE registry found a 3-year survival of only 33% in those with severe PH-COPD, defined as mPAP of 40 mmHg or greater [ 3 ].

Many recent studies have suggested that the burden of mortality in PH-COPD is at least as high if not higher than that of idiopathic PAH (IPAH), itself a disease with notoriously high mortality rates. A 2015 study of 1472 PH patients included in the COMPERA registry revealed a 3-year survival rate of 70.7% in IPAH but only 58.8% in PH-COPD [ 30 ]. Rates of mortality were noted to be lower at one, two, and three years in PH-COPD compared to PH-ILD. A 2019 study comparing 51 patients with PH due to chronic lung disease to 83 patients with IPAH demonstrated that the former patient group had equally poor outcomes despite lower mean pulmonary artery pressure and pulmonary vascular resistance [ 31 ]. A PVR of seven Wood units or greater was noted to confer a 3-fold higher risk of mortality and was more strongly associated with mortality than mPAP. Similar to the COMPERA registry above, 5-year survival was significantly lower amongst those with PH-ILD compared to PH-COPD.

In addition to markedly worsened overall survival, the presence of pulmonary artery enlargement on CT, implicative of higher mean pulmonary artery pressure, is associated with increased risk of severe COPD exacerbations requiring hospitalization [ 32 ].

3. Return to the Case Study

Given the presence of hypoxemia and severe dyspnea out of proportion to the spirometric defects present in the patient, as well as the severe defect in diffusion capacity, the possibility of significant pulmonary hypertension secondary to COPD is felt to be a reasonable diagnostic possibility. A repeat non-contrast CT scan of the chest that is obtained to evaluate for concurrent interstitial lung disease demonstrates emphysematous changes more prominent in the upper lobes; enlargement of the main pulmonary artery is also noted compared to on the last CT scan performed roughly one year prior for lung cancer screening.

A discussion between the patient, pulmonologist, and cardiologist is held regarding the risks and benefits of right heart catheterization, given that echocardiography suggested but could not estimate right heart pressures and a repeat CT scan demonstrated an interval increase in the width of the main pulmonary artery.

The patient consents to undergo right heart catheterization, which reveals a mean pulmonary artery pressure of 37 mmHg and a pulmonary capillary wedge pressure of 13 mmHg. Vasoreactivity testing was not performed. Alternative etiologies to explain this underlying pulmonary hypertension are discussed. The patient reveals he underwent polysomnography roughly two and a half years prior that did not demonstrate obstructive sleep apnea. A repeat STOP-BANG screening in clinic results in a score of 2, and the decision is made not to repeat sleep testing. A ventilation-perfusion scan to rule out chronic thromboembolic pulmonary disease (CTEPH) is considered, but the patient denies any history of thromboembolic disease.

Having effectively ruled out other likely contributing factors, the elevated right heart pressures are attributed to the known underlying lung disease and the diagnosis of severe PH-COPD is made. A trial of sildenafil (20 mg) three times daily is begun; after four weeks, the patient reports a mild improvement in exertional dyspnea but is noted to have a slight worsening in baseline oxygen saturation to 89%. Despite this change, he opts to continue the medication in light of his perception of a slight increase in exercise tolerance. In light of this worsening in baseline oxygen saturation, he is started on 2 L/min supplemental oxygen. He is offered referral to pulmonary rehabilitation but declines.

After six months, he returns to clinic and reports that both his ability to perform activities of daily living and his exertional dyspnea have not changed, though the purchase of a portable oxygen concentrator has made leaving his home easier. His oxygen saturation is 93% on 2 L/min in the office. A repeat echocardiogram is ordered that demonstrates continued moderate right ventricular systolic dysfunction, but mild dilatation of the ventricle compared to the moderate dilatation shown in the previous study; a tricuspid regurgitant jet again cannot be measured. A repeat six-minute walk distance is shown to be 37% of predicted from the 34% six months prior. In light of the patient’s lack of significant clinical improvement and his concerns of the cost of ongoing sildenafil therapy, the medication is stopped, and he is continued on his inhaled regimen for COPD and supplemental oxygen.

No external funding was provided for this review.

Conflicts of Interest

None of the authors disclose any conflicts of interest, either real or perceived.

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• Clinical Research Article
• Published: 31 August 2024

Biomarker screening for pulmonary hypertension in VLBW infants at risk for bronchopulmonary dysplasia

• Fernando A. Munoz   ORCID: orcid.org/0000-0001-8533-0292 1 ,
• Amanda Kim 1 ,
• Brendan Kelly 2 ,
• Emma Olson Jackson 3 ,
• Patrick D. Evers 2 ,
• Daniel Morrow 1 , 4 ,
• Amy McCammond 5 ,
• Brian K. Jordan 1   na1 &
• Brian Scottoline 1   na1  

Pediatric Research ( 2024 ) Cite this article

Metrics details

Very low birth weight (VLBW) infants demonstrate altered alveolar and pulmonary vascular development and carry an increased risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Risk stratification for BPD-associated PH (BPD-PH) in at-risk infants may help tailor management, improve outcomes, and optimize resource utilization.

VLBW infants were screened for PH with blood gas measurements, serum NT-proBNP and bicarbonate (HCO3) levels, and echocardiograms if they remained on respiratory support at 34 weeks corrected gestational age. We then tested 11 models using different cutoffs for NT-proBNP and HCO 3 to predict infants at low risk of BPD-PH.

We identified PH in 34 of 192 (17.6%) VLBW infants. The median NT-proBNP in VLBWs with PH was 2769 pg/mL versus 917 pg/mL in those without PH ( p  < 0.0001). A model with NT-proBNP < 950 pg/mL and HCO 3  < 32 mmol/L had a sensitivity of 100%, specificity of 34.2%, and negative predictive value of 100%. Using this model, 54 of 192 (28%) of the patients in this study would have been categorized as low risk for PH and could have avoided a screening echocardiogram.

NT-proBNP and HCO 3 together may serve as sensitive and cost-effective screening tools for BPD-PH in VLBW infants.

NT-proBNP and HCO 3 concentrations obtained together may help identify very low birth weight infants at risk for bronchopulmonary dysplasia who should undergo screening for pulmonary hypertension with echocardiography.

This large dataset demonstrates that NT-proBNP and HCO 3 levels together are more sensitive than NT-proBNP alone in identifying VLBW infants to undergo echocardiography.

The combination of NT-proBNP and HCO3 levels may identify VLBW infants at low risk for pulmonary hypertension and thus those who may be able to avoid screening echocardiography.

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Data availability.

The primary data may be provided upon reasonable request by contacting Dr. Brian Scottoline at [email protected]

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This work was supported by the National Heart Lung Blood Institute, K23. HL080231 (B.K.J.). B.S. is supported by the National Institute of Child Health and Development, R01 HD097367, R01 HD109193, and R44 HD112243. The funders had no role in study design, data collection, analysis, decision to publish, or manuscript preparation.

Author information

These authors contributed equally: Brian K. Jordan, Brian Scottoline.

Authors and Affiliations

Division of Neonatology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

Fernando A. Munoz, Amanda Kim, Daniel Morrow, Brian K. Jordan & Brian Scottoline

Division of Pediatric Cardiology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

Brendan Kelly & Patrick D. Evers

Heart Center, Seattle Children’s Hospital, Seattle, WA, USA

Emma Olson Jackson

PeaceHealth Sacred Heart Medical Center at Riverbend, Springfield, OR, USA

Daniel Morrow

Division of Pediatric Critical Care, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

Amy McCammond

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A.K., B.K., E.O.J., D.M., A.M., P.E., B.K.J., and B.S. contributed to the study conceptualization and data collection. F.A.M., A.K., P.E., B.K.J., and B.S. contributed to initial analysis and interpretation of the data. F.A.M., P.E., B.K.J., and B.S. drafted the initial manuscript. All authors critically revised and edited the manuscript. All authors approve the final version of the manuscript as submitted.

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Correspondence to Fernando A. Munoz .

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This study was approved by the OHSU IRB under IRB #11374 with waiver of consent.

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Munoz, F.A., Kim, A., Kelly, B. et al. Biomarker screening for pulmonary hypertension in VLBW infants at risk for bronchopulmonary dysplasia. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03517-5

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Received : 27 March 2024

Revised : 29 June 2024

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Published : 31 August 2024

DOI : https://doi.org/10.1038/s41390-024-03517-5

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