Background
Noninvasive calculation of pulmonary vascular resistance (PVR) has been reported to be feasible. We therefore evaluated whether baseline PVR could predict clinical outcomes in patients with acute pulmonary thromboembolism (aPTE).
Methods
The study cohort consisted of 54 patients with aPTE who underwent both pretreatment and follow-up echocardiography. Doppler-derived PVR was calculated using the following equation: PVR (Woods unit [WU]) = (peak tricuspid regurgitant velocity [TRV max ]/time-velocity integral of right ventricular outflow tract) × 10 + 0.16. Adverse clinical events included all-cause death and persistent pulmonary hypertension (TRV max >3.5 m/sec) on follow-up echocardiography.
Results
During a clinical follow-up time of 2.4 ± 1.7 years, 16 patients experienced adverse events (death [ n = 14]; persistent pulmonary hypertension [ n = 8]). Patients who developed adverse events were significantly older than those who did not (68.0 ± 13.8 years vs 56.9 ± 15.4 years, P = .02) and showed higher initial PVR (4.5 ± 1.4 WU vs 3.5 ± 1.0 WU, P = .01) and TRV max (3.9 ± 0.6 m/sec vs 3.6 ± 0.5 m/sec, P = .02). The best cutoff value of PVR for predicting adverse events was 4.5 WU (area under the curve = 0.71, P = .02), with a sensitivity and specificity of 63% and 90%, respectively. PVR >4.5 WU (hazard ratio 5.68; 95% CI, 1.89–16.95; P = .002) and older age (hazard ratio per 10 years = 1.47; 95% CI, 1.02–2.12; P = .04) were independent factors associated with the development of adverse events. The 6-year overall survival (16% ± 14% vs 87% ± 6%, P < .0001) and event-free survival (15% ± 13% vs 84% ± 6%, P < .0001) rates differed according to initial PVR.
Conclusion
Echocardiographic estimation of PVR provides important prognostic information in patients with aPTE.
Acute pulmonary thromboembolism (aPTE) is characterized by a sudden increase in afterload on the right ventricle that is proportional to the degree of obstruction of the pulmonary vascular bed, with death and other adverse clinical events usually resulting from hemodynamic compromise due to an acute increase in pulmonary vascular resistance (PVR). Noninvasive echocardiographic estimation of PVR has been reported to be feasible, and the clinical significance of such testing in several pulmonary vascular diseases is being examined. We hypothesized that PVR measured at initial clinical presentation might be a useful prognostic indicator in patients with aPTE. To test this hypothesis, clinical data on patients with aPTE who underwent repeated echocardiography and clinical evaluation were analyzed.
Materials and Methods
This study was conducted after appropriate institutional review board approval. The study cohort consisted of 54 patients (33 female, mean age 60.1 ± 15.6 years) with aPTE who underwent both pretreatment and follow-up echocardiography between January 2002 and December 2006. Patients with active vasculitis involving the heart or great vessels were excluded. Most patients ( n = 44) were diagnosed by contrast-enhanced computed tomography, and the others ( n = 10) underwent perfusion scans, mainly because of underlying renal failure. All patients were initially treated with therapeutic doses of unfractionated or low-molecular-weight heparin for at least 7 days, followed by warfarin, a vitamin K antagonist, with the goal of attaining and holding an international normalized ratio of 2.0 to 3.0 for at least 6 months. Further anticoagulation treatment was at the discretion of each attending physician.
Echocardiography
All patients underwent comprehensive two-dimensional and Doppler echocardiographic evaluation on the day of or the day after confirmatory diagnosis of aPTE, using a Hewlett-Packard (Palo Alto, CA) Sonos 2500 or 5500 imaging system equipped with a 2.5-MHz transducer. Two-dimensionally derived left ventricular (LV) ejection fraction was determined by the biplane method of discs. Total LV volume is calculated from the summation of a stack of elliptical disks. The height of each disk is calculated as a fraction (usually 1/20) of the LV long axis based on the longer of the two lengths from the two- and four-chamber views.
An integrated approach was used for evaluation of tricuspid regurgitation (TR) and the right heart chambers. The severity of TR was determined by considering jet area by color flow imaging, continuous-wave Doppler-derived spectral jet density and contour, and pulsed-wave Doppler recording of hepatic vein flow. The right heart chambers were evaluated by measuring RV and right atrial area, and by calculating RV fractional area change, defined as (end-diastolic area – end-systolic area)/end-diastolic area × 100, which was used for objective assessment of RV systolic function. Fractional area change was obtained by tracing the RV endocardium in both end-systole and end-diastole. The TR jet velocity was used to estimate peak systolic pulmonary artery pressure, with the peak tricuspid regurgitant velocity (TRV max ), as measured by continuous-wave Doppler, representing peak systolic right ventricular (RV) or pulmonary artery pressure for estimation of the degree of pulmonary hypertension: Right atrial pressure was estimated by diameter change of inferior vena cava during respiration. The time velocity integral of systolic flow through the right ventricular outflow tract (TVI RVOT ) was obtained by placing the sample volume just proximal to the pulmonary valve. Doppler-derived PVR was calculated using the following equation ( Figure 1 )
PVR (Woods unit [WU]) = (TRV max /TVI RVOT ) × 10 + 0.16.
Clinical Evaluation
To evaluate the severity of aPTE, we included data on arterial oxygen pressure and arterial oxygen saturation at the time of aPTE diagnosis. We also reviewed initial images of contrast-enhanced computed tomography or perfusion scan to evaluate whether aPTE involved both lung fields.
All patients were followed up 1 month after discharge and every 1 or 3 months thereafter. Clinical data were collected by review of medical records or telephone interview. The primary outcomes included all-cause death and persistent pulmonary hypertension, defined as TRV max >3.5 m/sec, on follow-up echocardiography performed at least 2 months after the initial acute pulmonary thromboembolism. All deaths were defined as of cardiovascular origin unless an unequivocal noncardiovascular cause was established. Information on deaths was obtained from the registry of the National Health Insurance Corporation, which assigns a unique personal identification number to each patient. All patients underwent follow-up echocardiography, with persistent pulmonary hypertension assessed echocardiographically at least 2 months after the initial diagnosis of acute pulmonary thromboembolism.
Statistical Analysis
Categoric variables are presented as raw numbers and percentages, and compared using the chi-square test for equality of proportions. Continuous variables are shown as means ± standard deviations, and compared by Student t test. The Kaplan–Meier method was used to determine event-free survival rate, and differences between groups were assessed using the log-rank test. Predictors for time-to-event were assessed by univariate and multivariate Cox regression analysis. Results were adjusted for significant differences in patient characteristics using Cox proportional hazards regression models, which included all variables with P values < .2 by univariate analysis. The covariates of baseline characteristics included all variables listed in Table 1 . The optimal cutoff value for predicting adverse events, defined as that with the maximal sum of sensitivity and specificity, was determined using receiver-operating characteristic curve analysis; thus, PVR (>4.5 WU vs ≤4.5 WU) and TRV max (>3.5 m/sec vs ≤3.5 m/sec) were included as dichotomous variables. A second multivariate Cox model, used to identify predictors of adverse clinical outcomes, used backward elimination. P values <.05 were considered statistically significant. All statistical analyses were performed with SPSS version 12.0 for Windows (SPSS Inc., Chicago, IL).
| Total ( n = 54) | Event (+) ( n = 16) | Event (-) ( n = 38) | P value | |
|---|---|---|---|---|
| Age (y) | 60 ± 16 | 68 ± 14 | 57 ± 15 | .02 |
| Women, n (%) | 33 (61%) | 10 (63%) | 23 (61%) | .89 |
| Diabetes mellitus, n (%) | 4 (7%) | 0 (0%) | 4 (11%) | .18 |
| Hypertension, n (%) | 17 (31%) | 4 (25%) | 13 (34%) | .51 |
| Smoker, n (%) | 13 (24%) | 5 (31%) | 8 (21%) | .42 |
| Hemoglobin (g/dL) | 13.4 ± 2.5 | 13.3 ± 2.2 | 13.4 ± 2.6 | .84 |
| Creatinine (mg/dL) | 1.0 ± 0.4 | 1.1 ± 0.6 | 0.9 ± 0.3 | .29 |
| Arterial O 2 saturation (%) | 93 ± 7 | 90 ± 7 | 94 ± 6 | .02 |
| Arterial O 2 pressure (mm Hg) | 63 ± 14 | 53 ± 10 | 67 ± 13 | .001 |
| Associated clinical conditions, n (%) | ||||
| Surgery | 9 (17%) | 1 (6%) | 8 (21%) | |
| Malignancy | 5 (9%) | 1 (6%) | 4 (11%) | |
| Trauma | 4 (7%) | 1 (6%) | 3 (8%) | |
| Oral contraceptive | 2 (4%) | 0 (0%) | 2 (5%) | |
| Bedridden state | 1 (2%) | 1 (6%) | 0 (0%) | |
| Antiphospholipid antibody syndrome | 1 (2%) | 0 (0%) | 1 (3%) | |
| LV ejection fraction (%) | 63 ± 7 | 61 ± 10 | 64 ± 5 | .19 |
| RV end–diastolic area (cm ) | 26 ± 5 | 27 ± 7 | 25 ± 4 | .35 |
| RV end–systolic area (cm ) | 21 ± 5 | 23 ± 7 | 20 ± 4 | .20 |
| RV fractional area change (%) | 26.3 ± 11.1 | 25.5 ± 12.2 | 26.7 ± 10.9 | .74 |
| RV fractional area change <35% | 42 (79%) | 12 (80%) | 30 (79%) | .93 |
| TR grade ≥3 | 21 (39%) | 9 (56%) | 12 (32%) | .09 |
| Peak TRV (m/sec) | 3.7 ± 0.5 | 3.9 ± 0.6 | 3.6 ± 0.5 | .02 |
| Peak TRV >3.5 m/sec | 31 (57%) | 13 (81%) | 18 (47%) | .03 |
| TVI of RVOT flow (cm) | 11.0 ± 2.8 | 9.9 ± 3.0 | 11.5 ± 2.6 | .07 |
| PVR (WU) | 3.8 ± 1.2 | 4.5 ± 1.4 | 3.5 ± 1.0 | .01 |
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