Patients with severe pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) can now be identified using three widely available clinical variables, all of which can be measured non-invasively, a single-center, retrospective analysis indicates.
“All PH is prognostically relevant in COPD, but severe PH is associated with severely decreased survival, and it is frequently associated with a different phenotype of COPD, with less severe airway obstruction but more severe diffusion [capacity] and more severe hypoxemia as well,” Gabor Kovacs, MD, associate professor of pulmonology, Medical University of Graz, Graz, Austria, explained to Medscape Medical News.
“We believe that patients with this specific phenotype might benefit from individualized therapy, but we need to identify them first and we need non-invasive tools to [select out] patients with this phenotype from the large number of COPD patients without it,” he added.
The study was published online January 26 in the journal CHEST.
Suspected Pulmonary Hypertension
A total of 142 patients with COPD who had undergone clinically indicated right heart catheterization for suspected PH were included in the analysis. “The diagnosis of COPD and the severity of airflow limitation were established according to the GOLD [Global Initiative for Chronic Obstructive Lung Disease] recommendations,” Kovacs and colleagues note.
Stratified for severity of PH, 74 participants had severe PH, 45 had moderate PH, and only 23 patients had no PH, investigators observed.
COPD with severe PH was defined as a mean pulmonary arterial pressure (mPAP) ≥ 35 mm Hg or mPAP ≥ 25 mm Hg with a low cardiac index of less than 2.0 L/min/m2. COPD with moderate PH was defined as mPAP 25-34 mm Hg or mPAP of 21-24 mm Hg with pulmonary vascular resistance (PVR) ≥ 3 Wood Units (WU). COPD without PH was defined as a MPAP < 21 mm Hg or mPAP of 21-24 mm Hg with a PVR < 3 WU.
Three independent predictive variables were included in the multivariable prediction model for severe PH:
Systolic pulmonary arterial pressure (sPAP) ≥ 56 mmHg, estimated by echocardiography
N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels ≥ 650 pg/mL
The ratio of the main pulmonary artery/ascending aorta diameter at the tubular site (PA/Ao-ratio) in chest CT ≥ 0.93
When all three criteria were met — which occurred in one third of the cohort — the specificity of the predictive model was 94.9% and the positive predictive value for severe PH was 93.5%. In fact, the presence of at least one of the criteria (84% of cases) had a sensitivity of 98.2% and most patients with COPD and severe PH could be detected by the recognition of a severe elevation in PAP, investigators noted.
“By contrast, if none of them was present…the probability of severe PH was only 6.7%,” the authors note. Indeed, the multivariable prediction model outperformed echocardiography, according to their report. The authors pointed out that they did not include body mass index (BMI) into their original prediction model even though BMI was elevated in patients with severe PH.
However, when they did add a BMI of 28.4 kg/m2 or higher to the original three variables, “every COPD patient in our cohort in whom all four criteria were met…had severe PH and no COPD patient had severe PH in whom none of the criteria were met,” the authors observe.
At a median follow-up of 3.7 years, slightly more than half of the cohort had died, and three patients had received a lung transplant. The median time to the combined endpoint of death or lung transplantation was 5.9 years from baseline. After adjusting for age and sex in the multivariable model, both airflow limitation and severity of PH were independently associated with survival and each of these two factors contributed equally to increased mortality risk, investigators observe.
Specifically, airflow limitation diagnosed as GOLD stage 3 was associated with a 56% higher risk of death (hazard ratio [HR], 1.56) compared with patients with an airflow limitation of GOLD stage 1 to 2. For patients with an airflow limitation meeting the criteria for GOLD stage 4, the risk of death was 3.4 times higher (HR, 3.45) compared with patients with GOLD stage 1 to 2 disease.
Similarly, patients with severe PH had an 85% higher risk of death (HR, 1.85) compared with patients who did not have PH. When the combination of airflow limitation defined as GOLD stage 3 to 4 vs GOLD stage 1 to 2 and non-severe vs severe PH were analyzed, three different prognostic groups (P = 004) could be identified, investigators noted.
These groups included “good prognosis” patients who had a GOLD grade 1 to 2 diagnosis and nonsevere PH among whom 90% were still alive at 3 years. Some 68% of patients with an “intermediate prognosis” including those with either a GOLD stage 3 or 4 diagnosis or severe PH similarly were alive at 3 years, whereas 54% of patients with a “poor prognosis” — defined as having a combination of GOLD stage 3 to 4 disease and severe PH — were alive at 3 years, they added.
“In the multivariable analysis, only 6-minute walk distance (6MWD; P < .001) and systemic vascular resistance index (P = .018) remained significant independent predictors of prognosis,” the authors noted — the best prognostic cutoffs for a poor prognosis being a 6MWD < 200 meters and a systemic vascular resistance index < 2800 dyn·s·cm-5m2. At baseline, 61% of patients with severe PH were receiving a drug for the treatment of pulmonary arterial hypertension (PAH) compared with only 27% of those with moderate PH (P < .001).
Hemodynamics were perhaps expectedly worse in treated patients than in untreated patients, yet survival was not significantly different between the two groups, researchers observed. As Kovacs noted, “First of all, it’s important that all patients with COPD receive optimal treatment” — perhaps a banal observation, he added, but one which is not always observed.
Then, if a patient still has relevant symptoms despite optimal treatment and if they have severe PH, “they should be included in clinical trials of PAH if there are any,” he added. Unfortunately, no drug has yet been approved for use in patients with severe PH and COPD, Kovacs noted.
However, “there may be a subset of patients who may benefit from PAH therapy, and for this subset of patients treatment needs to be individualized and patients referred to expert centers where a decision about treatment may be made between the physician and the patient,” Kovacs said.
Limitations of the study include its retrospective nature and findings need to be validated in independent cohorts, the authors point out.
The recent INCREASE study carried out in patients with interstitial lung disease and PH, again as documented by right heart catheterization, as reported in the New England Journal of Medicine in January 2021, showed that those who received inhaled treprostinil (Tyvaso) had a significant increase in the 6MWD compared with placebo patients (P < .001) and there was a 15% reduction in NT-proBNP levels from baseline to week 16 compared with a 46% increase in NT-proBNP levels with placebo (P < .001).
More placebo patients (about one third) also showed signs of clinical worsening at study endpoint compared with about one quarter of those in the treprostinil group. Another trial, the PERFECT trial, is currently evaluating the inhaled form of treprostinil in patients with COPD and PH.
Asked to comment on the findings, Steven Cassady, MD, assistant professor of medicine, University of Maryland School of Medicine, Baltimore, noted that this study is important in that it strengthens the use of other noninvasive methods for PH detection in COPD beyond echocardiography alone, which can be less reliable in patients with advanced lung disease.
“This patient phenotype described by Dr Kovacs — namely COPD with pulmonary hypertension, low diffusion capacity, and more severe hypoxemia — is in desperate need of therapeutic options, Cassady told Medscape Medical News in an email. “Use of these findings could allow for earlier detection of severe COPD and PH as well as referral to specialty centers for individualized PH therapy and enrollment in trials,” he said.
Cassady also felt the current study’s findings could help answer the ongoing question of which specific COPD patients with severe PH could benefit from pulmonary vasodilator therapy.
Kovacs reports receiving personal fees from Actelion, Janssen, Bayer, GlaxoSmithKline, MSD, Boehringer Ingelheim, Novartis, Chiesi, Vitalaire, Ferrer, and AOP. Several co-authors disclosed relationships with industry. The full list can be found with the original article.
CHEST. Published online January 26, 2022. Full text
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