Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Early use of echocardiography in patients with acute pulmonary embolism: Findings from the RIETE registry

Background\u2014Transthoracic echocardiography (TTE) is often considered for risk stratification of patients with acute pulmonary embolism (PE). We sought to determine the contemporary utilization of early TTE (within 72 hours of PE diagnosis) and explored the association between TTE findings and PE-related mortality. Methods and Results\u2014Data from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry, a multicenter registry of consecutive patients with acute PE, were used (2001-July 2017). We used a generalized linear mixed model to determine predictors of early TTE performance. Moreover, the association between 3 TTE variables (right atrial enlargement, right ventricular hypokinesis, and presence of right heart thrombi) and 30-day PE-related mortality was assessed in generalized linear mixed models adjusted for PE severity index, and other comorbidities. Among 35 935 enrollees with acute PE, 15 375 (42.8%) underwent early TTE. There was an increase in early TTE utilization rate over time (P<0.001 for trend). Younger age, female sex, enrollment in countries other than Spain, history of coronary disease, heart failure, atrial fibrillation, tachycardia, and hypotension were the main predictors of early TTE (P<0.01 for all). In multivariable analyses, right atrial enlargement (adjusted odds ratio: 3.74; 95% confidence interval, 2.10-6.66), right ventricular hypokinesis (adjusted odds ratio: 3.11, 95% confidence interval: 1.85-5.21) and right heart thrombi (adjusted odds ratio: 4.39, 95% confidence interval, 1.99-9.71) were associated with increased odds for PErelated mortality. Conclusions\u2014Early TTE is commonly performed for acute PE and utilization rates have increased over time. Right atrial enlargement, right ventricular hypokinesis, and right heart thrombi are predictive of worse outcomes. Clinical Trial Registration\u2014URL: http://www.clinicaltrials.gov. Unique identifier: NCT02832245

Heart Rate and Mortality in Patients With Acute Symptomatic Pulmonary Embolism

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE

Treatment of Right Heart Thrombi Associated with Acute Pulmonary Embolism

Background Evidence-based recommendations do not adequately address the treatment of right heart thrombi in patients who present with acute symptomatic pulmonary embolism. Methods This study included patients who had acute pulmonary embolism associated with right heart thrombi and participated in the Registro Informatizado de la Enfermedad TromboEmb\uf3lica registry. We assessed the effectiveness of anticoagulation versus reperfusion treatment for the outcomes of all-cause mortality, pulmonary embolism\u2013related mortality, recurrent venous thromboembolism, and major bleeding rates through 30 days after initiation of pulmonary embolism treatment. We used propensity score matching to adjust for the likelihood of receiving reperfusion treatment. Results Of 325 patients with pulmonary embolism and right heart thrombi, 255 (78%; 95% confidence interval, 74-83) received anticoagulation and 70 (22%; 95% confidence interval, 17-26) also received reperfusion treatment. Propensity score\u2013matched pairs analyses did not detect a statistically lower risk of all-cause death (6.2% vs 14%, P&nbsp;= .15) or pulmonary embolism\u2013related mortality (4.7% vs 7.8%; P&nbsp;= .47) for reperfusion compared with anticoagulation. Of the patients who received reperfusion treatment, 6.2% had a recurrence during the study follow-up period, compared with 0% of those who received anticoagulation (P&nbsp;= .049). The incidence of major bleeding events was not statistically different between the 2 treatment groups (3.1% vs 3.1%; P&nbsp;= 1.00). Conclusions In patients with pulmonary embolism and right heart thrombi, no significant difference was found between reperfusion therapy and anticoagulant therapy for mortality and bleeding. The risk of recurrences was significantly higher for reperfusion therapy compared with anticoagulation. Right heart thrombi may not warrant riskier interventions than standard anticoagulation

Incidence of major adverse cardiovascular events among patients with provoked and unprovoked venous thromboembolism: Findings from the Registro Informatizado de Enfermedad Tromboemb\uf3lica Registry

Objective: Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE. Methods: We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboemb\uf3lica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel &gt;6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the \u3c72 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of &lt;.05 was considered statistically significant. Results: We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE. Conclusions: Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events

Systolic blood pressure and mortality in acute symptomatic pulmonary embolism

BACKGROUND: The optimal cutoff for systolic blood pressure (SBP) level to define high-risk pulmonary embolism (PE) remains to be defined. METHODS: To evaluate the relationship between SBP levels on admission and mortality in patients with acute symptomatic PE, the current study included 39,257 consecutive patients with acute symptomatic PE from the RIETE registry between 2001 and 2018. Primary outcomes included all-cause and PE-specific 30-day mortality. Secondary outcomes included major bleeding and recurrent venous thromboembolism (VTE). RESULTS: There was a linear inverse relationship between admission SBP and 30-day all-cause and PE-related mortality that persisted after multivariable adjustment. Patients in the lower SBP strata had higher rates of all-cause death (reference: SBP 110-129 mmHg) (adjusted odds ratio [OR] 2.9; 95% confidence interval [CI], 2.0-4.2 for SBP 190 mmHg). Consistent findings were also observed for 30-day PE-related death. CONCLUSIONS: In patients with acute symptomatic PE, a low SBP portends an increased risk of all-cause and PE-related mortality. The highest mortality was observed in patients with SBP <70 mmHg.status: publishe

PREAMI: Perindopril and remodelling in elderly with acute myocardial infarction: Study rationale and design

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, the development of remodeling, left ventricular (LV) dysfunction, and ischemic events, both when administered alone as long-term treatment in patients with impaired LV function and/or heart failure (HF) and as short-term treatment, early after acute myocardial infarction (AMI) and/or HF. The few data available on the use of ACE inhibitors in the elderly after AMI are conflicting. Nothing is known about the effects of ACE inhibitors in elderly postinfarction patients with preserved LV function: these patients have a remarkable medium- to long-term mortality and HF incidence after infarction. The aim of this study is to evaluate, in patients with AMI aged ≥65 years, the effects of Perindopril on the combined outcome of death, hospitalization for HF, and heart remodeling, considered to be a ≥8% increase in LV end-diastolic volume (LVEDV). Secondary objectives include the same factors listed in the primary end points hut considered separately. In addition, safety of the drug, ventricular remodeling, and adaptation are being evaluated. A total of 1100 patients with AMI (first episode or reinfarction), aged ≥65 years, and preserved or only moderately depressed LV (LV ejection fraction ≥40%), are to he enrolled and randomly assigned to treatment (8 mg for 12 months of Perindopril or placebo, in double-blind conditions). Clinical assessment is performed at fixed times, and periodic evaluations of (1) ventricular shape, dimensions, and function by quantitative 2-D echocardiography, and (2) heart rate variability and arrhythmias by ambulatory electrocardiographic monitoring are anticipated. The results and conclusions will be available by 2002 year