Objectives:

Pulmonary arterial hypertension (PAH) is a rare and progressive disease associated with increased pulmonary vascular resistance that, if unrelieved, progresses to right ventricular pressure overload, dysfunction, right heart failure, and premature death. PAH is more prevalent in some populations, thereby warranting screening of asymptomatic individuals. This review seeks to evaluate the comparative validity, reliability, and feasibility of echocardiography and biomarker testing for the screening, diagnosis, and management of PAH; to clarify whether the use of echocardiography or biomarkers affects decisionmaking and clinical outcomes; and to determine which medications are effective for treating PAH and whether combination therapy is more effective than monotherapy.

Data sources:

We searched PubMed^®, Embase^®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies.

Review methods:

Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded the strength of evidence. Random-effects models were used to compute summary estimates of effect where several similar studies provided estimates.

Results:

Sixty studies involving 7,096 patients evaluated biomarker tests, echocardiography, or both to screen for PAH. Symptom status of study populations consisted of asymptomatic (3 studies; 481 patients), symptomatic (41 studies; 4,394 patients), mixed (8 studies; 1,186 patients), and symptoms not described (8 studies; 1,035 patients). N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed moderate correlation with right heart catheterization (RHC) hemodynamic measures and a great deal of variability between studies in its diagnostic accuracy and discrimination; however, one good-quality prospective cohort study suggested that biomarker testing with NT-proBNP might be useful in ruling out PAH in patients with symptoms suggestive of PAH who have elevated systolic pulmonary artery pressure (sPAP) by echocardiography. No data are available regarding combined echocardiography and biomarker screening in asymptomatic patients at high risk for PAH. Echocardiography estimates of pulmonary artery pressures (sPAP, tricuspid gradient [TG], and tricuspid regurgitant jet velocity [TRV]) and PVR (TRV/velocity-time integral of right ventricular outflow tract [VTI_RVOT]) demonstrated good accuracy in screening for PAH, but accuracy varied with the prevalence of PAH in study populations.

Ninety-nine studies involving 8,655 patients evaluated biomarker tests, echocardiography, or both to evaluate severity or prognosis and followed progression of disease or response to therapy. B-type natriuretic peptide (BNP) showed moderate correlation with most RHC measures (mean pulmonary artery pressure [mPAP], PVR, cardiac index, right atrial pressure [RAP]) and clinical measures of disease severity (6-minute walk distance [6MWD]) and showed weak correlation with pulmonary capillary wedge pressure (PCWP), indicating that BNP levels alone could not serve as an accurate surrogate marker for disease severity. Echocardiography-derived sPAP showed strong correlation with RHC-sPAP with a precise summary effect estimate, although there was a great deal of heterogeneity of results among individual studies. BNP level (summary hazard ratio [HR] 2.42; 95% confidence interval [CI], 1.72 to 3.41) and presence of pericardial effusion were strong predictors of mortality (summary HR 2.43; 95% CI, 1.57 to 3.77) RA size and uric acid were also predictive of mortality, but fractional area change (FAC) showed no significant ability to predict mortality, and data on TAPSE were insufficient.

Thirty-seven studies involving 4,192 patients assessed the effectiveness of drug treatments for PAH in adults. Few deaths were observed in these limited duration studies, leading to wide CIs and lack of statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6WMD when compared with placebo, but comparisons between agents were inconclusive. Combination therapy also showed improved 6WMD compared with monotherapy, but the diversity of treatment regimens and the small number of combination therapy trials again make comparisons between specific regimens inconclusive. The odds ratio (OR) of hospitalization was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR 0.34 and 0.48, respectively), while the reduction in patients taking prostanoids compared with placebo was similar but not statistically significant. Each drug class showed a favorable impact on at least two of the three hemodynamic outcomes: cardiac index, mPAP, and PVR.

The applicability of these findings is limited by the relative lack of diagnostic studies among asymptomatic patients and, in prognostic and diagnostic studies, inadequate description and apparent diversity of disease etiology and severity.

Conclusions:

Further confirmation is needed to determine if the combination of echocardiography and the biomarker NT-proBNP is sufficiently accurate to rule out PAH when testing symptomatic patients. In asymptomatic populations, more research is needed to permit conclusions regarding their effectiveness for screening. BNP, RA size, presence of pericardial effusion, and uric acid had prognostic value in patients with PAH, but other echocardiographic parameters and biomarkers either were not predictive or had insufficient data. Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Comparisons of different drug combinations were inconclusive regarding a mortality reduction but suggested an improvement in 6MWD when a second drug was added to existing monotherapy.