Optimal hemodynamic parameters for risk stratification in acute pulmonary embolism patients.

Hemodynamic assessment of patients with pulmonary embolism (PE) remains a fundamental component of early risk stratification that in turn, influences subsequent monitoring and therapeutic strategies. The current body of literature and international evidence-based clinical practice guidelines focus mainly on the use of systolic blood pressure (SBP). The accuracy of this single hemodynamic parameter, however, and its optimal values for the identification of hemodynamic instability have been recently questioned by clinicians. For example, abnormal SBP or shock index may be a late indicator of adverse outcomes, signaling a patient in whom the cascade of hemodynamic compromise is already well underway. The aim of the present article is to review the current evidence supporting the use of SBP and analyze the potential integration of other parameters to assess the hemodynamic stability, impending clinical deterioration, and guide the reperfusion treatment in patients with PE, as well as to suggest potential strategies to further investigate this issue.

Implications of Mean Pulmonary Arterial Wedge Pressure Trajectories in Pulmonary Arterial Hypertension.

Rationale: The mean pulmonary arterial wedge pressure (mPAWP) is the critical hemodynamic factor differentiating group 1 pulmonary arterial hypertension (PAH) from group 2 pulmonary hypertension associated with left heart disease. Despite the discrepancy between the mPAWP upper physiologic normal and current PAH definitions, the implications of the initial mPAWP for PAH clinical trajectory are poorly understood. Objectives: To model longitudinal mPAWP trajectories in PAH over 10 years and examine the clinical and hemodynamic factors associated with trajectory membership. Methods: Adult patients with PAH with two or more right heart catheterizations were identified from a multiinstitution healthcare system in eastern Massachusetts. mPAWP trajectories were constructed via group-based trajectory modeling. Feature selection was performed in least absolute shrinkage and selection operator regression. Logistic regression was used to assess associations between trajectory membership, baseline characteristics, and transplant-free survival. Measurements and Main Results: Among 301 patients with PAH, there were two distinct mPAWP trajectories, termed "mPAWP-high" (n = 71; 23.6%) and "mPAWP-low" (n = 230; 76.4%), based on the ultimate mPAWP value. Initial mPAWP clustered around median 12 mm Hg (interquartile range [IQR], 8-14 mm Hg) in the mPAWP-high and 9 mm Hg (IQR, 6-11 mm Hg) in the mPAWP-low trajectories (P < 0.001). After feature selection, initial mPAWP ⩾12 mm Hg predicted an mPAWP-high trajectory (odds ratio, 3.2; 95% confidence interval, 1.4-6.1; P = 0.0006). An mPAWP-high trajectory was associated with shorter transplant-free survival (vs. mPAWP-low, median, 7.8 vs. 11.3 yr; log-rank P = 0.017; age-adjusted P = 0.217). Conclusions: Over 10 years, the mPAWP followed two distinct trajectories, with 25% evolving into group 2 pulmonary hypertension physiology. Using routine baseline data, longitudinal mPAWP trajectory could be predicted accurately, with initial mPAWP ⩾12 mm Hg as one of the strongest predictors.

Advanced Imaging in Pulmonary Vascular Disease.

Although the diagnosis of pulmonary hypertension requires invasive testing, imaging serves an important role in the screening, classification, and monitoring of patients with pulmonary vascular disease (PVD). The development of advanced imaging techniques has led to improvements in the understanding of disease pathophysiology, noninvasive assessment of hemodynamics, and stratification of patient risk. This article discusses the current role of advanced imaging and the emerging novel techniques for visualizing the lung parenchyma, mediastinum, and heart in PVD.

Clinical trials in group 3 pulmonary hypertension.

PURPOSE OF REVIEW: Despite worse outcomes associated with the development of pulmonary hypertension in chronic lung disease, there are no approved treatments for this population. The present review summarizes the recent clinical trials in World Symposium on Pulmonary Hypertension (WSPH) Group 3 pulmonary hypertension, with a particular focus on the study of pulmonary arterial hypertension (PAH)-targeted therapy. RECENT FINDINGS: Multiple recent randomized controlled trials have studied a host of PAH-specific medications in the treatment of WSPH Group 3 pulmonary hypertension, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. In pulmonary hypertension associated with chronic obstructive lung disease (PH-COPD) and with interstitial lung disease (PH-ILD), most trials have shown conflicting or negative results, although they have been limited by variable patient populations and small sample sizes. Recent large-scale trial data demonstrate that inhaled treprostinil is associated with improved outcomes in the PH-ILD population. SUMMARY: Although most PAH medications have not shown consistent benefit in the WSPH Group 3 population, recent work suggests that inhaled treprostinil has an important role in the treatment of PH-ILD. Efforts are ongoing to evaluate the efficacy of other medications, identify optimal treatment candidates, and define clinically meaningful endpoints in WSPH Group 3 pulmonary hypertension.

Primary cardiac hospitalizations in pulmonary arterial hypertension: Trends and outcomes from 2001 to 2014.

BACKGROUND: Hospitalizations in pulmonary arterial hypertension (PAH) are common and are often for cardiac conditions. Using the National (Nationwide) Inpatient Sample (NIS), we examined characteristics and mortality of primary cardiac hospitalizations in PAH from 2001 to 2014. METHODS: Adult hospitalizations with any diagnosis code for PAH were identified. Primary cardiac disease was defined as a primary discharge diagnosis of congestive heart failure (CHF), pulmonary heart disease, coronary atherosclerosis, acute myocardial infarction, dysrhythmia, conduction disorder, cardiomyopathy or carditis, heart valve disorder, or cardiac arrest. Temporal trends, characteristics, and in-hospital mortality were analyzed. RESULTS: From 2001 to 2014, there were 207,095 hospitalizations in PAH, of which 100,509 (48.5%) carried a primary cardiac diagnosis. Most primary cardiac hospitalizations in PAH were for CHF, and pneumonia was the most common primary non-cardiac diagnosis. Over the study period, primary cardiac hospitalizations in PAH fell from 52.9% to 41.4% (p < 0.001). CHF was the most frequent primary cardiac diagnosis associated with death, with sepsis representing the most common primary non-cardiac disease (1,226; 25.0%). Overall, the mortality in primary cardiac hospitalizations in PAH was 5.3% (vs. in primary non-cardiac, 6.9%, p < 0.001). On multivariable analysis, a primary cardiac discharge diagnosis remained associated with a decreased risk of death (odds ratio 0.85, p = 0.010). CONCLUSION: Primary cardiac hospitalizations in PAH are common and are associated with decreased mortality compared to admissions for primary non-cardiac diagnoses.

Hospitalizations with hereditary hemorrhagic telangiectasia and pulmonary hypertension in the United States from 2000 to 2014.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease that causes widespread abnormal vasculature development, resulting in multiple complications including pulmonary hypertension (PH). Despite the potential severity of PH, there is a lack of data on hospitalization characteristics and outcomes in the HHT-PH population. The purpose of this analysis was to describe trends and outcomes of HHT-PH hospitalizations within the National (Nationwide) Inpatient Sample (NIS). METHODS: Adult hospitalizations (age ≥18 years) with a principal or secondary diagnosis of HHT were identified from the 2000-2014 NIS. Records were stratified by a concurrent PH diagnosis. Trends, characteristics, and outcomes of hospitalizations with HHT and PH were analyzed. RESULTS: There were 55,189 adult hospitalizations with HHT from 2000 to 2014, of which 4602 (8.3%) had a concurrent diagnosis of PH. HHT-PH hospitalizations rose steadily from 165 (5.1%) in 2000 to 540 (13.8%) in 2014 (p < 0.001). They were more common in females (vs. HHT without PH, 71.6% vs. 59.2%, p < 0.001) and were associated with a higher comorbidity burden (total 4.0 ±â€¯0.1 vs. 2.4 ±â€¯0.03, p < 0.001). Inpatient mortality was higher in HHT-PH hospitalizations than in HHT without PH (3.5% vs. 1.8%, p < 0.001). On multivariable logistic regression, the diagnosis of PH remained significantly associated with a higher risk of inpatient death (odds ratio 1.71, 95% confidence interval 1.11-2.63, p = 0.015) in HHT hospitalizations. CONCLUSIONS: HHT-PH hospitalizations rose from 2000 to 2014. Notably, HHT patients with a concurrent PH diagnosis were at significantly higher risk of in-hospital mortality.

Clinical Probability Tools for Deep Venous Thrombosis, Pulmonary Embolism, and Bleeding.

Overdiagnosis of venous thromboembolism is associated with increasing numbers of patient complications and health care burden. Multiple clinical tools exist to estimate the probability of pulmonary embolism and deep venous thrombosis. When used with d-dimer testing, these can further stratify venous thromboembolism risk to help inform the use of additional diagnostic testing. Although there are similar tools to estimate bleeding risk, these are not as well-validated and lack reliability.

Dose-Volume Predictors of Esophagitis After Thoracic Stereotactic Body Radiation Therapy.

OBJECTIVES: Esophageal toxicity has become a major concern as stereotactic hypofractionated radiation therapy is increasingly utilized for central pulmonary tumors. Our purpose was to define esophageal dosimetric parameters that predict potentially dose-limiting toxicities. MATERIALS AND METHODS: In total, 157 patients with a planning target volume ≤5 cm from the esophagus were selected from an institutional database. Toxicity was scored with the CTCAE v4.0. Esophageal Dmax and Dv (dose D in Gy covering volume v in mL) in 0.5 mL increments were collected. Corresponding biologically effective dose (BED) was calculated for α/ß=10,3 (BED10, BED3). Normal tissue complication probability was computed with conventionally fractionated radiotherapy parameters and equivalent dose in 2 Gy per fraction (EQD2). Dosimetric predictors were identified with multivariate logistic regression with a manual forward stepwise selection technique. RESULTS: The grade≥2 esophagitis rate was 5.7%. BED10 to 1.5 mL was the best predictor of esophagitis. BED10 to 0.5, 1.0, 2.0, 3.0, and 3.5 mL were also predictive but less strong. Results were similar when BED3 and physical dose were examined. Tumor-esophageal distance correlated with esophagitis (10.5% risk of≥grade 2 events with distance≤3.9 cm vs. 1.3% when>3.9 cm, P=0.016). BED10 to 1.5 mL correlated well with EQD2 normal tissue complication probability estimates. CONCLUSIONS: BED to 1.5 mL was the strongest predictor of grade≥2 esophagitis (independent of α/ß ratio) with a 10.6% toxicity risk when BED10>21.1 Gy (14.3 Gy in 3 fractions, 16.0 Gy in 5). The overall rate of severe toxicity is low, suggesting that higher doses may be tolerable.

The Effect of Biologically Effective Dose and Radiation Treatment Schedule on Overall Survival in Stage I Non-Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.

PURPOSE: To determine the effect of biologically effective dose (BED10) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED10 and radiation treatment schedule. The linear-quadratic equation was used to calculate BED10 and to generate a dichotomous dose variable of <105 Gy versus ≥105 Gy BED10. The primary outcome was OS. We used the Kaplan-Meier method, the log-rank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED10 was associated with OS. RESULTS: We identified 747 patients who met inclusion criteria. The median BED10 was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving ≥105 Gy BED10 had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED10 had a median survival of 22 months (log-rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED10 ≥105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high- and low-dose cohorts confirmed a survival benefit with higher prescription dose. CONCLUSIONS: We found that dose escalation to 105 Gy BED10 and beyond may improve survival in NSCLC patients treated with SBRT.

Elderly patients undergoing SBRT for inoperable early-stage NSCLC achieve similar outcomes to younger patients.

OBJECTIVES: It is unclear whether elderly patients face an increased risk of complications following stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC), as has been reported following surgical resection. This study evaluates toxicity and outcomes achieved with SBRT in elderly versus non-elderly patients. MATERIALS AND METHODS: We retrospectively identified patients treated with SBRT for cT1-3N0M0 NSCLC between 2007 and 2013. We defined elderly and non-elderly cohorts by age ≥75 and <75. We used chi-square and logistic regression analyses to compare toxicity, and employed Kaplan-Meier, log-rank, and multivariable Cox proportional hazard analyses to assess overall survival (OS), local control (LC), and distant control (DC). RESULTS: We identified 251 patients (126 elderly, 125 non-elderly) with a median follow-up of 3.0 years. No differences in acute or late grade ≥3 toxicity were observed. Acute grade ≥3 toxicity was 11.1% in elderly vs. 8.0% in non-elderly (p=0.66). Late grade ≥3 toxicity was 10.3% in elderly vs. 7.2% in non-elderly (p=0.50). There was one grade 5 toxicity (hemoptysis). There were no 3-year OS or LC differences between elderly and non-elderly patients (OS 47.5% vs. 41.0%, p=0.75; LC 84.2% vs. 86.4%, p=0.89). However, 3-year DC was superior in elderly patients (89.1% vs. 76.0%, p=0.01). Improved DC remained associated with elderly age in Cox regression (HR 0.42, p=0.01). CONCLUSION: Elderly patients undergoing SBRT for early stage NSCLC appear to have similar risk of toxicity and rate of efficacy as in younger patients. These findings support the use of SBRT in appropriately selected elderly patients.

Pulmonary dose-volume predictors of radiation pneumonitis following stereotactic body radiation therapy.

PURPOSE: Radiation pneumonitis (RP) may be severe after stereotactic body radiation therapy. Our purpose was to identify pulmonary and cardiac dosimetric parameters that predicted for post-stereotactic body radiation therapy grade ≥2 RP. METHODS AND MATERIALS: A total of 335 patients with ≥3 months' follow-up were included. Normal pulmonary volume was total lungs minus gross tumor volume. Pulmonary maximum dose, mean lung dose (MLD), and the percent of lung receiving ≥x Gy for 5 to 50 Gy in 5-Gy increments were collected. Cardiac maximum dose, mean dose, volume of lung receiving ≥0.1 Gy (V0.1), V0.25 to V1, and V2.5 to V12.5 were recorded. Multivariable logistic regression with manual backward stepwise elimination was used to identify the best dosimetric predictors of toxicity. Optimal dose-volume cutoffs were isolated with recursive partitioning analysis (RPA). RESULTS: The grade ≥2 RP rate was 18.8%. Pulmonary V5 to V50, MLD, and cardiac V0.1 to V2.5 were significantly associated with toxicity on univariate analysis. On multivariable logistic regression, V10 was the strongest dosimetric predictor of grade ≥2 RP (odds ratio, 1.052; 95% confidence interval, 1.014-1.092; P = .007). RPA identified a 21.6% risk of grade ≥2 RP with V10 ≥6.14% (vs 3.8% with <6.14). MLD was the most significant predictor of grade ≥3 RP (odds ratio, 1.002; 95% confidence interval, 1.000-1.003; P = .031). RPA identified a 25.0% risk of grade ≥3 RP with MLD ≥7.84 Gy (vs 8.0% when <7.84 Gy). CONCLUSIONS: With a grade ≥2 RP rate of 18.8%, lung V10 was the best predictor of grade ≥2 toxicity. MLD was the best predictor of grade ≥3 RP.

Angiotensin-converting enzyme inhibitors decrease the risk of radiation pneumonitis after stereotactic body radiation therapy.

PURPOSE: Although angiotensin-converting enzyme (ACE) inhibitor use during conventionally fractionated radiation therapy has been associated with a decreased risk of radiation pneumonitis (RP), a similar effect has not been demonstrated in stereotactic body radiation therapy (SBRT). The purpose of this study was to examine the impact of ACE inhibitor use during SBRT on the risk of symptomatic (grade ≥2) RP. METHODS AND MATERIALS: Patients with at least 1 follow-up treated with SBRT for primary lung cancer were included. ACE inhibitors, angiotensin receptor blockers, statins, nonsteroidal anti-inflammatory drugs, and glucocorticoids were examined. RP was determined from all available medical records, including follow-up appointments with radiation oncology, pulmonology, medical oncology, and hospitalizations. It was scored with the Common Terminology Criteria for Adverse Events, version 4.0. Analysis was performed with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: A total of 257 patients met inclusion criteria. Seventy (27.2%) used an ACE inhibitor during SBRT. The overall rates of grade ≥2 and ≥3 RP were 19.1% (n = 49) and 7.0% (n = 18), respectively. ACE inhibitor users experienced greater freedom from symptomatic RP on univariate (vs nonusers, 89.8% vs 76.3% at 12 months, P = .029) and multivariate analysis (hazard ratio 0.373, 95% confidence interval 0.156-0.891, P =.026). The volume of normal lung tissue receiving ≥5 Gy, %, ≥10 Gy, ≥20 Gy, and mean lung dose were also significantly associated with RP on univariate and multivariate analysis. ACE inhibitor use was not associated with overall survival. Angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, glucocorticoids, and statin administration were not associated with symptomatic RP or survival. CONCLUSIONS: ACE inhibitor use during SBRT was associated with significantly greater freedom from grade ≥2 RP, even after adjusting for pulmonary dose. Given the data on their protective effect in human and animal models, a prospective evaluation is warranted.

Central versus Peripheral Tumor Location: Influence on Survival, Local Control, and Toxicity Following Stereotactic Body Radiotherapy for Primary Non-Small-Cell Lung Cancer.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) has been increasingly utilized for medically inoperable early stage non-small-cell lung cancer. However, a lower biological equivalent dose (BED) is often used for central tumors given toxicity concerns, potentially leading to decreased local control (LC). We compared survival, LC, and toxicity outcomes for SBRT patients with centrally versus peripherally located tumors. METHODS: We included patients with primary cT1-2N0M0 non-small-cell lung cancer treated with SBRT at our institution from September 2007 to August 2013 with follow-up through August 2014. Central tumor location was defined as within 2 cm of the proximal bronchial tree, heart, great vessels, trachea, or other mediastinal structures. Kaplan-Meier analysis and multivariable Cox regression modeling were used for overall survival (OS) and LC, and the χ test and multivariable logistic regression modeling were used for toxicity. RESULTS: We included 251 patients (111 central, 140 peripheral) with median follow-up of 31.2 months. Patients with central tumors were more likely to be older (mean 75.8 versus 73.5 years; p = 0.04), have larger tumors (mean 2.5 cm versus 1.9 cm; p < 0.001), and be treated with a lower BED (mean 120.2 Gy versus 143.5 Gy; p < 0.001). Multivariable analysis revealed that tumor location was not associated with worse OS, LC, or toxicity. Patients with central tumors were less likely to have acute grade greater than or equal to three toxicity than those with peripheral tumors (odds ratio: 0.24; p = 0.02). CONCLUSIONS: Central tumor location did not predict for inferior OS, LC, or toxicity following SBRT when a lower mean BED was utilized.