Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial.

Thrombotic antiphospholipid syndrome (TAPS) is characterized by venous, arterial, or microvascular thrombosis. Patients with TAPS merit indefinite anticoagulation, and warfarin has historically been the standard treatment. Apixaban is an oral factor Xa inhibitor anticoagulant that requires no dose adjustment or monitoring. The efficacy and safety of apixaban compared with warfarin for TAPS patients remain unknown. This multicenter prospective randomized open-label blinded endpoint study assigned anticoagulated TAPS patients to apixaban or warfarin (target international normalized ratio 2-3) for 12 months. The primary efficacy outcome was clinically overt thrombosis and vascular death. Apixaban was first given at 2.5 mg twice daily. Two protocol changes were instituted based on recommendations from the data safety monitoring board. After the twenty-fifth patient was randomized, the apixaban dose was increased to 5 mg twice daily, and after the thirtieth patient was randomized, subjects with prior arterial thrombosis were excluded. Primary outcomes were adjudicated by independent experts blinded to treatment allocation. Patients randomized between 23 February 2015 and 7 March 2019 to apixaban (n = 23) or warfarin (n = 25) were similar. Among the components of the primary efficacy outcome, only stroke occurred in 6 of 23 patients randomized to apixaban compared with 0 of 25 patients randomized to warfarin. The study ended prematurely after the forty-eighth patient was enrolled. Conclusions from our study are limited due to protocol modifications and low patient accrual. Despite these limitations, our results suggest that apixaban may not be routinely substituted for warfarin to prevent recurrent thrombosis (especially strokes) among patients with TAPS. This trial was registered at www.clinicaltrials.gov as #NCT02295475.

Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Enrollment Characteristics and 1-Year Follow-up.

BACKGROUND: The United States Chronic Thromboembolic Pulmonary Hypertension Registry (US-CTEPH-R) was designed to characterize the demographic characteristics, evaluation, clinical course, and outcomes of surgical and nonsurgical therapies for patients with chronic thromboembolic pulmonary hypertension. RESEARCH QUESTION: What are the differences in baseline characteristics and 1-year outcomes between operated and nonoperated subjects? STUDY DESIGN AND METHODS: This study describes a multicenter, prospective, longitudinal, observational registry of patients newly diagnosed (< 6 months) with CTEPH. Inclusion criteria required a mean pulmonary artery pressure ≥ 25 mm Hg documented by right heart catheterization and radiologic confirmation of CTEPH. Between 2015 and 2018, a total of 750 patients were enrolled and followed up biannually until 2019. RESULTS: Most patients with CTEPH (87.9%) reported a history of acute pulmonary embolism. CTEPH diagnosis delays were frequent (median, 10 months), and most patients reported World Health Organization functional class 3 status at enrollment with a median mean pulmonary artery pressure of 44 mm Hg. The registry cohort was subdivided into Operable patients undergoing pulmonary thromboendarterectomy (PTE) surgery (n = 566), Operable patients who did not undergo surgery (n = 88), and those who were Inoperable (n = 96). Inoperable patients were older than Operated patients; less likely to be obese; have a DVT history, non-type O blood group, or thrombophilia; and more likely to have COPD or a history of cancer. PTE resulted in a median pulmonary vascular resistance decline from 6.9 to 2.6 Wood units (P < .001) with a 3.9% in-hospital mortality. At 1-year follow-up, Operated patients were less likely treated with oxygen, diuretics, or pulmonary hypertension-targeted therapy compared with Inoperable patients. A larger percentage of Operated patients were World Health Organization functional class 1 or 2 at 1 year (82.9%) compared with the Inoperable (48.2%) and Operable/No Surgery (56%) groups (P < .001). INTERPRETATION: Differences exist in the clinical characteristics between patients who exhibited operable CTEPH and those who were inoperable, with the most favorable 1-year outcomes in those who underwent PTE surgery. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02429284; URL: www.clinicaltrials.gov.

Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances.

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as a broader recognition of extrapulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and focus on the early initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is an early diagnosis for prompt initiation of treatment to achieve a minimal symptom burden; optimize the patient's biochemical, hemodynamic, and functional profile; and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underused approaches to PAH management include a novel TGF-ß ligand trap pharmacotherapy, remote pulmonary arterial pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary arterial denervation. These and other PAH state of the art advances are summarized here for the wider pulmonary medicine community.

The United States Chronic Thromboembolic Pulmonary Hypertension Registry: Protocol for a Prospective, Longitudinal Study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequela of acute pulmonary embolism that is treatable when recognized. Awareness of this disease has increased with recent advancements in therapeutic options, but delays in diagnosis remain common, and diagnostic and treatment guidelines are often not followed. Data gathered from international registries have improved our understanding of CTEPH, but these data may not be applicable to the US population owing to differences in demographics and medical practice patterns. OBJECTIVE: The US CTEPH Registry (US-CTEPH-R) was developed to provide essential information to better understand the demographics, risk factors, evaluation, and treatment of CTEPH in the United States, as well as the short- and long-term outcomes of surgical and nonsurgical therapies in the modern treatment era. METHODS: Thirty sites throughout the United States enrolled 750 subjects in this prospective, longitudinal, observational registry of patients newly diagnosed with CTEPH. Enrollment criteria included a mean pulmonary artery pressure ≥25 mmHg by right heart catheterization and radiologic confirmation of CTEPH by a multidisciplinary adjudication committee. Following enrollment, subjects were followed biannually until the conclusion of the study. Quality of life surveys were administered at enrollment and biannually, and all other testing was at the discretion of the treating clinician. Details regarding surgical therapy, balloon pulmonary angioplasty, and medical therapy were collected at enrollment and at follow-up, as well as information related to health care utilization and survival. RESULTS: Data from this registry will improve understanding of the demographics, risk factors, and treatment patterns of patients with CTEPH, and the longitudinal impact of therapies on quality of life, health care utilization, and survival. CONCLUSIONS: This manuscript details the methodology and design of the first large, prospective, longitudinal registry of patients with CTEPH in the United States. TRIAL REGISTRATION: ClinicalTrials.gov NCT02429284; https://www.clinicaltrials.gov/ct2/show/NCT02429284. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25397.

Development and Validation of an Abridged Version of the REVEAL 2.0 Risk Score Calculator, REVEAL Lite 2, for Use in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Achievement of low-risk status is a treatment goal in pulmonary arterial hypertension (PAH). Risk assessment often is performed using multiparameter tools, such as the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator. Risk calculators that assess fewer variables without compromising validity may expedite risk assessment in the routine clinic setting. We describe the development and validation of REVEAL Lite 2, an abridged version of REVEAL 2.0. RESEARCH QUESTION: Can a simplified version of the REVEAL 2.0 risk assessment calculator for patients with PAH be developed and validated? STUDY DESIGN AND METHODS: REVEAL Lite 2 includes six noninvasive variables-functional class (FC), vital signs (systolic BP [SBP] and heart rate), 6-min walk distance (6MWD), brain natriuretic peptide (BNP)/N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and renal insufficiency (by estimated glomerular filtration rate [eGFR])-and was validated in a series of analyses (Kaplan-Meier, concordance index, Cox proportional hazard model, and multivariate analysis). RESULTS: REVEAL Lite 2 approximates REVEAL 2.0 at discriminating low, intermediate, and high risk for 1-year mortality in patients in the REVEAL registry. The model indicated that the most highly predictive REVEAL Lite 2 parameter was BNP/NT-proBNP, followed by 6MWD and FC. Even if multiple, less predictive variables (heart rate, SBP, eGFR) were missing, REVEAL Lite 2 still discriminated among risk groups. INTERPRETATION: REVEAL Lite 2, an abridged version of REVEAL 2.0, provides a simplified method of risk assessment that can be implemented routinely in daily clinical practice. REVEAL Lite 2 is a robust tool that provides discrimination among patients at low, intermediate, and high risk of 1-year mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies.

BACKGROUND: Pulmonary arterial hypertension is a progressive, fatal disease. Published treatment guidelines recommend treatment escalation on the basis of regular patient assessment with the goal of achieving or maintaining low-risk status. Various strategies are available to determine risk status. This analysis describes an update of the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk calculator (REVEAL 2.0) and compares it with recently published European Society of Cardiology/Respiratory Society guideline-derived risk assessment strategies. METHODS: A subpopulation from the US-based registry REVEAL that survived ≥ 1 year postenrollment (baseline for this cohort) was analyzed. For REVEAL 2.0, point values and cutpoints were reassessed, and new variables were evaluated. The Kaplan-Meier method was used to estimate survival at 12 months postbaseline; discrimination was quantified using the c-statistic. Mortality estimates and discrimination were compared between REVEAL 2.0 and Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and French Pulmonary Hypertension Registry (FPHR) risk assessment strategies. For this comparison, a three-category REVEAL 2.0 score was computed in which patients were classified as low-, intermediate-, or high-risk. RESULTS: REVEAL 2.0 demonstrated similar discrimination as the original calculator in this subpopulation (c-statistic = 0.76 vs 0.74), provided excellent separation of risk among the risk categories, and predicted clinical worsening as well as mortality in patients who were followed ≥ 1 year. The REVEAL 2.0 three-category score had greater discrimination (c-statistic = 0.73) than COMPERA (c-statistic = 0.62) or FPHR (c-statistic = 0.64). Compared with REVEAL 2.0, COMPERA and FPHR both underestimated and overestimated risk. CONCLUSIONS: REVEAL 2.0 demonstrates greater risk discrimination than the COMPERA and FPHR risk assessment strategies in patients enrolled in REVEAL. After external validation, the REVEAL 2.0 calculator can assist clinicians and patients in making informed treatment decisions on the basis of individual risk profiles. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00370214; URL: www.clinicaltrials.gov.

Baseline and Serial Brain Natriuretic Peptide Level Predicts 5-Year Overall Survival in Patients With Pulmonary Arterial Hypertension: Data From the REVEAL Registry.

BACKGROUND: Plasma brain natriuretic peptide (BNP) level is a prognostic biomarker in pulmonary arterial hypertension (PAH). Its impact on long-term overall survival (OS) was investigated in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL), a 5-year observational, multicenter, US registry of patients with PAH. METHODS: Patients were ≥ 18 years of age, met right heart catheterization criteria at rest, had World Health Organization group I PAH, and had BNP measurement at enrollment. Optimal BNP threshold was obtained via receiver operating characteristic curve analysis. OS was compared in patients with low (≤ 340 pg/mL) vs high (> 340 pg/mL) BNP at baseline; changes between baseline and last assessment were also examined. Patients were categorized based on baseline (low or high) and follow-up (low or high) BNP values; hazard ratios (HRs) for OS were estimated and compared using Cox regression. RESULTS: Overall, 1,426 patients were analyzed. Mortality risk was significantly higher in patients with baseline high vs low BNP (HR, 3.6; 95% CI, 3.0-4.2). BNP change analysis at ≤ 1 year postenrollment demonstrated that the low-low group had the lowest and the high-high group had the highest 5-year mortality risk (HR, 0.23; 95% CI, 0.19-0.27). Changes in BNP score also correlated with change of risk of death. CONCLUSIONS: Baseline BNP threshold of 340 pg/mL strongly predicted survival up to 5 years in patients with PAH. A BNP reduction at 1 year since enrollment was associated with decreased mortality risk, whereas an increase in BNP at 1 year was associated with an increased mortality risk, supporting BNP as a surrogate marker of PAH survival.

Computerized clinical decision support improves warfarin management and decreases recurrent venous thromboembolism.

BACKGROUND: An explicit approach to warfarin dose adjustment using computerized clinical decision support (CDS) improves warfarin management. We report metrics of quality for warfarin management before and after implementation of CDS in a large health care system. METHODS: A total of 2591 chronically anticoagulated patients were eligible for inclusion. We compared interpatient time in therapeutic range (TTR) and international normalized ratio (INR) variability before and after implementation of CDS. We report outcomes of major bleeding, thrombosis, and health care utilization. RESULTS: Implementation of CDS significantly improved TTR (from 63.99% to 65.13%; P = .04) and reduced out-of-range INRs (from 42.39% to 39.97%; P < .001). Venous thromboembolism (relative risk [RR] 0.41; P < .001) emergency department utilization (RR 0.62; P < .001), and hospitalization (RR 0.62; P < .001) were reduced after CDS implementation. Major hemorrhage was more frequent after CDS implementation (RR 1.42; P = .01). CONCLUSION: The CDS warfarin management was associated with improved TTR and decreased INR variability in a large cohort of chronically anticoagulated patients. Clinically relevant outcomes were broadly improved, although more bleeding events were observed.

Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.

BACKGROUND: The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL Registry) was established to provide updated characteristics of patients with pulmonary arterial hypertension (PAH) and to improve diagnosis, treatment, and management. METHODS: Fifty-four US centers enrolled consecutively screened patients with World Health Organization group I PAH who met expanded hemodynamic criteria of mean pulmonary arterial pressure (PAP) > 25 mm Hg at rest (30 mm Hg with exercise), pulmonary capillary wedge pressure (PCWP) or= 240 dynes x s x cm(-5). Patients meeting the traditional hemodynamic definition (PCWP

Computer surveillance of patients at high risk for and with venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), may be the number one preventable cause of death associated with hospitalization. Numerous evidence-based guidelines for effective VTE prophylaxis therapy exist. However, underuse is common due to the difficulty in integrating VTE risk assessment into routine patient care. Previous studies utilizing computer decision support to identify high-risk patients report improved use of prophylaxis therapy and reduced VTE. However, those studies did not report the sensitivity, specificity or positive predictive value of their methods to identify patients at high risk. We report an evaluation of a computerized tool to identify patients at high risk for VTE that found a sensitivity of 98% and positive predictive value of 99%. Another computer program used to detect VTE had a sensitivity of 92%, specificity of 99% and a positive predictive value of 97% to identify DVT and a sensitivity of 100%, specificity of 98% and positive predictive value of 89% to identify PE. These tools were found to provide a dependable method to identify patients at high risk for and with VTE.