Randomised controlled trial of a prognostic assessment and management pathway to reduce the length of hospital stay in normotensive patients with acute pulmonary embolism.

BACKGROUND: The length of hospital stay (LOS) for acute pulmonary embolism (PE) varies considerably. Whether the upfront use of a PE prognostic assessment and management pathway is effective in reducing the LOS remains unknown. METHODS: We conducted a randomised controlled trial of adults hospitalised for acute PE: patients were assigned either to a prognostic assessment and management pathway involving risk stratification followed by predefined criteria for mobilisation and discharge (intervention group) or to usual care (control group). The primary end-point was LOS. The secondary end-points were the cost of prognostic tests and of hospitalisation, and 30-day clinical outcomes. RESULTS: Of 500 patients who underwent randomisation, 498 were included in the modified intention-to-treat analysis. The median LOS was 4.0 days (interquartile range (IQR) 3.7-4.2 days) in the intervention group and 6.1 days (IQR 5.7-6.5 days) in the control group (p<0.001). The mean total cost of prognostic tests was EUR 174.76 in the intervention group, compared with EUR 233.12 in the control group (mean difference EUR -58.37, 95% CI EUR -84.34- to -32.40). The mean total hospitalisation cost per patient was EUR 2085.66 in the intervention group, compared with EUR 3232.97 in the control group (mean difference EUR -1147.31, 95% CI EUR -1414.97- to -879.65). No significant differences were observed in 30-day readmission (4.0% versus 4.8%), all-cause mortality (2.4% versus 2.0%) or PE-related mortality (0.8% versus 1.2%) rates. CONCLUSIONS: The use of a prognostic assessment and management pathway was effective in reducing the LOS for acute PE.

Adjusted D-dimer cutoff levels to rule out pulmonary embolism in patients hospitalized for COPD exacerbation: results from the SLICE trial.

BACKGROUND: For patients with suspected pulmonary embolism (PE), age- or clinically-adjusted D-dimer threshold level can be used to define a negative test that safely excludes PE and reduces the use of imaging. However, the utility of this approach in patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbation is undefined. METHODS: We ran an analysis of the patients hospitalized for COPD exacerbation and randomized to the intervention in the SLICE trial. Using the conventional strategy as the reference, we compared the proportion of patients with a negative D-dimer result, and the negative predictive value and sensitivity of three D-dimer threshold strategies for initial PE or subsequent diagnosis of venous thromboembolism (VTE): the age-adjusted strategy, the Wells-adjusted strategy, and the YEARS-adjusted strategy. RESULTS: We included 368 patients. Using a conventional threshold, 182 (49.5%) patients had negative D-dimer values, of whom 1 (0.6%) had PE (sensitivity, 94.1%). The use of an age-adjusted threshold increased the number of patients in whom PE could be excluded from 182 to 233 patients (63.3%), and the proportion of false-negative findings increased from 0.5% to 1.7% (sensitivity, 76.5%). With the use of the Wells or YEARS strategies, 64.4% and 71.5% had negative values, and the proportion of false-negative findings was 2.5% (sensitivity, 64.7%) and 2.7% (sensitivity, 58.8%), respectively. CONCLUSIONS: In patients hospitalized for COPD exacerbation, compared with the conventional strategy, age- or clinically-adjusted strategies of D-dimer interpretation were associated with a larger proportion of patients in whom PE was ruled out with a higher failure rate. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02238639 .

Efficacy and safety outcomes of recanalisation procedures in patients with acute symptomatic pulmonary embolism: systematic review and network meta-analysis.

BACKGROUND: We aimed to review the efficacy and safety of recanalisation procedures for the treatment of PE. METHODS: We searched PubMed, the Cochrane Library, EMBASE, EBSCO, Web of Science and CINAHL databases from inception through 31 July 2015 and included randomised clinical trials that compared the effect of a recanalisation procedure versus each other or anticoagulant therapy in patients diagnosed with PE. We used network meta-analysis and multivariate random-effects meta-regression to estimate pooled differences between each intervention and meta-regression to assess the association between trial characteristics and the reported effects of recanalisation procedures versus anticoagulation. RESULTS: For all-cause mortality, there were no significant differences in event rates between any of the recanalisation procedures and anticoagulant treatment (full-dose thrombolysis: OR 0.60; 95% CI0.36 to 1.01; low-dose thrombolysis: 0.47; 95% CI 0.14 to 1.59; and catheter-associated thrombolysis: 0.31; 95% CI 0.01 to 7.96). Full-dose thrombolysis increased the risk of major bleeding (2.00; 95% CI 1.06 to 3.78) compared with anticoagulation. Catheter-directed thrombolysis was associated with the lowest probability of dying (surface under the cumulative ranking curve (SUCRA), 0.67), followed by low-dose thrombolysis (SUCRA, 0.66) and full-dose thrombolysis (SUCRA, 0.55). Similarly, low-dose thrombolysis was associated with the lowest probability of major bleeding (SUCRA, 0.61), followed by catheter-directed thrombolysis (SUCRA, 0.54) and full-dose thrombolysis (SUCRA, 0.17). The results were similar in sensitivity analyses based on restricting only to studies in haemodynamically stable patients with PE. CONCLUSIONS: In the treatment of PE, recanalisation procedures do not seem to offer a clear advantage compared with standard anticoagulation. Low-dose thrombolysis was associated with the lowest probability of dying and bleeding. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015024670.

Management appropriateness and outcomes of patients with acute pulmonary embolism.

The impact of adherence to published guidelines on the outcomes of patients with acute pulmonary embolism (PE) has not been well defined by previous studies.In this prospective cohort study of patients admitted to a respiratory department (n=2096), we evaluated whether patients with PE had better outcomes if they were acutely managed according to international guidelines. Outcomes consisted of all-cause mortality, PE-related mortality, recurrent venous thromboembolism (VTE) and major bleeding events during the first month of follow-up after diagnosis.Overall, 408 patients (19% (95% CI 18-21%)) did not receive guideline-adherent PE management. Patients receiving non-adherent management were significantly more likely to experience all-cause mortality (adjusted odds ratio (OR) 2.39 (95% CI 1.57-3.61) or PE-related mortality (adjusted OR 5.02 (95% CI 2.42-10.42); p<0.001) during follow-up. Non-adherent management was also a significant independent predictor of recurrent VTE (OR 2.19 (95% CI 1.11-4.32); p=0.03) and major bleeding (OR 2.65 (95% CI 1.66-4.24); p<0.001). An external validation cohort of 34 380 patients with PE from the RIETE registry confirmed these findings.PE management that does not adhere to guidelines for indications related to anticoagulation, thrombolytics and inferior vena cava filters is associated with worse patient outcomes.

Prognostic impact of copeptin in pulmonary embolism: a multicentre validation study.

To externally validate the prognostic impact of copeptin, either alone or integrated in risk stratification models, in pulmonary embolism (PE), we performed a post hoc analysis of 843 normotensive PE patients prospectively included in three European cohorts.Within the first 30 days, 21 patients (2.5%, 95% CI 1.5-3.8) had an adverse outcome and 12 (1.4%, 95% CI 0.7-2.5) died due to PE. Patients with copeptin ≥24 pmol·L-1 had a 6.3-fold increased risk for an adverse outcome (95% CI 2.6-15.5, p<0.001) and a 7.6-fold increased risk for PE-related death (95% CI 2.3-25.6, p=0.001). Risk classification according to the 2014 European Society of Cardiology (ESC) guideline algorithm identified 248 intermediate-high-risk patients (29.4%) with 5.6% (95% CI 3.1-9.3) at risk of adverse outcomes. A stepwise biomarker-based risk assessment strategy (based on high-sensitivity troponin T, N-terminal pro-brain natriuretic peptide and copeptin) identified 123 intermediate-high-risk patients (14.6%) with 8.9% (95% CI 4.5-15.4) at risk of adverse outcomes. The identification of patients at higher risk was even better when copeptin was measured on top of the 2014 ESC algorithm in intermediate-high-risk patients (adverse outcome OR 11.1, 95% CI 4.6-27.1, p<0.001; and PE-related death OR 13.5, 95% CI 4.2-43.6, p<0.001; highest risk group versus all other risk groups). This identified 85 patients (10.1%) with 12.9% (95% CI 6.6-22.0) at risk of adverse outcomes and 8.2% (95% CI 3.4-16.2) at risk of PE-related deaths.Copeptin improves risk stratification of normotensive PE patients, especially when identifying patients with an increased risk of an adverse outcome.

Assessment of right ventricular function in acute pulmonary embolism.

The optimal approach to assess right ventricular (RV) function in patients with acute symptomatic pulmonary embolism (PE) lacks clarity. METHODS: This study aimed to evaluate the optimal approach to assess RV function in normotensive patients with acute symptomatic PE. Outcomes assessed through 30-days after the diagnosis of PE included all-cause mortality and complicated course. RESULTS: Eight hundred forty-eight patients were enrolled. Multidetector computed tomography (MDCT) and transthoracic echocardiography agreed on the presence or absence of RV overload in 449 (53%) patients. The combination of the simplified Pulmonary Embolism Severity Index (sPESI) and MDCT showed a negative predictive value for 30-day all-cause mortality of 100%. Of the 43% that had an sPESI of >0 points and MDCT RV enlargement, 41 (11.3%) experienced a complicated course that included 24 (6.6%) deaths. One hundred twenty-nine patients (15%) had an sPESI of >0 points, MDCT, and echocardiographic RV overload. Of these, 21 (16.3%) experienced a complicated course within the first 30days, and 10 (7.7%) of them died. CONCLUSIONS: Incorporation of echocardiographic RV overload to the sPESI and MDCT did not improve identification of low-risk PE patients, whereas it improved identification of those at intermediate-high risk for short-term complications.

Prognostic Scores for Acute Pulmonary Embolism.

Rapid and accurate risk stratification is critical in determining the optimal treatment strategy for patients with acute pulmonary embolism (PE). Early identification of patients with normal blood pressure and a favorable prognosis (low-risk PE) might select a subset of patients for outpatient treatment, which is associated with reduced cost and improved patient satisfaction, and has been shown to be effective and safe. Alternatively, identification of normotensive patients deemed as having a high risk for PE-related adverse clinical events (intermediate-high-risk PE) might select a subset of patients for close observation and consideration of escalation of therapy. Clinical prognostic scores have been gaining importance in the classification of patients into these categories. They should be derived and validated following strict methodological standards, and their use in clinical practice should be encouraged.

Right heart thrombi in pulmonary embolism.

There is a lack of comprehensive data on the prevalence, predictors and prognostic significance of right heart thrombi (RHT) in pulmonary embolism.In this study of patients with pulmonary embolism from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry, we assessed the prevalence and predictors of RHT, and the association between the presence of RHT and the outcomes of all-cause mortality, pulmonary embolism-related mortality, recurrences, and major bleeding through 30 days after initiation of pulmonary embolism treatment.Of 12 441 patients with pulmonary embolism and baseline echocardiographic data, 2.6% had RHT. The following increased the risk of RHT: younger age, previous bleeding, congestive heart failure, cancer, syncope, systolic blood pressure <100 mmHg, and arterial oxyhaemoglobin saturation <90%. Patients with RHT were significantly more likely to die from any cause (adjusted OR 2.50 (95% CI 1.62-3.84); p<0.001) and from pulmonary embolism (adjusted OR 4.29 (95% CI 2.45-7.48); p<0.001) during follow-up. RHT was associated with an increased risk of recurrence during follow-up (1.8% versus 0.7%; p=0.04). Major bleeding was similar in patients with and without RHT.In patients presenting with pulmonary embolism, RHT is relatively infrequent. Patients with RHT had a worse outcome when compared with those without RHT.

Integration of Extracorporeal Membrane Oxygenation into the Management of High-Risk Pulmonary Embolism: An Overview of Current Evidence.

High-risk pulmonary embolism (PE) refers to a large embolic burden causing right ventricular failure and hemodynamic instability. It accounts for approximately 5% of all cases of PE but contributes significantly to overall PE mortality. Systemic thrombolysis is the first-line revascularization therapy in high-risk PE. Surgical embolectomy or catheter-directed therapy is recommended in patients with an absolute contraindication to systemic thrombolysis. Extracorporeal membrane oxygenation (ECMO) provides respiratory and hemodynamic support for the most critically ill PE patients with refractory cardiogenic shock or cardiac arrest. The complex management of these individuals requires urgent yet coordinated multidisciplinary care. In light of existing evidence regarding the utility of ECMO in the management of high-risk PE patients, a number of possible indications for ECMO utilization have been suggested in the literature. Specifically, in patients with refractory cardiac arrest, resuscitated cardiac arrest, or refractory shock, including in cases of failed thrombolysis, venoarterial ECMO (VA-ECMO) should be considered, either as a bridge to percutaneous or surgical embolectomy or as a bridge to recovery after surgical embolectomy. We review here the current evidence on the use of ECMO as part of the management strategy for the highest-risk presentations of PE and summarize the latest data in this indication.

C-reactive Protein and Risk of Right Ventricular Dysfunction and Mortality in Patients With Acute Symptomatic Pulmonary Embolism.

BACKGROUND: Right ventricle (RV) dysfunction increases the risk of death from pulmonary embolism (PE). C-reactive protein (CRP) might identify RV inflammation and dysfunction in patients with PE. METHODS: This cohort study enrolled consecutive stable patients with acute PE between 2017 and 2023. We stratified patients by quartiles of CRP. We evaluated the association between CRP quartiles and the presence of RV dysfunction, and used multivariable models to assess for an association between CRP and the outcomes of all-cause and PE-specific mortality during the 30 days of follow-up after PE diagnosis. RESULTS: The study included 633 stable patients with PE. Patients without RV dysfunction had significantly lower median (IQR) CRP levels compared with patients with RV dysfunction (n=509, 31.7 [10.0-76.4]mg/L vs n=124, 45.4 [16.0-111.4]mg/L; P=0.018). CRP showed a statistically significant positive association with the presence of RV dysfunction (P<0.01). On multivariable analysis, CRP level was not significantly associated with 30-day all-cause mortality (adjusted odds ratio [OR] per mg/L increment, 1.00; 95% CI, 1.00-1.01; P=0.095), but higher CRP was associated with significantly higher PE-related mortality (adjusted OR, 1.01; 95% CI, 1.00-1.01; P=0.026). Compared with patients in CRP quartile 1, patients in quartiles 2, 3, and 4 had a stepwise increase in the adjusted odds of 30-day all-cause death of 2.41 (P=0.148), 3.04 (P=0.062), and 3.15 (P=0.052), respectively. CONCLUSIONS: As an indicator of RV dysfunction, CRP may improve risk stratification algorithms for hemodynamically stable patients with acute symptomatic PE.

Chronic thromboembolic pulmonary hypertension treatment and sex: Systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic pulmonary hypertension leading to right heart failure and death. While pulmonary endarterectomy is the treatment of choice, some patients might benefit from medical therapy or balloon pulmonary angioplasty. Sex differences in outcomes of these therapies are not well characterized. MATERIAL AND METHODS: We conducted a systematic review and meta-analysis to investigate sex differences in outcomes of various therapies for CTEPH. We searched MEDLINE, PubMed, Embase, CINAHL and the Cochrane Library databases between January 1, 2010 and April 30, 2021, published in English. We pooled incidence estimates using random-effects meta-analyses. We evaluated heterogeneity using the I2 statistic. We assessed publication bias using Begg's and Egger's tests. This study is registered in PROSPERO, CRD42021268504. RESULTS: A total of 19 studies met the eligibility criteria, but only 3 trials provided separate outcomes for women and men. Two studies evaluated the efficacy of BPA, and one study evaluated the efficacy of riociguat (129 patients). Overall, 57.3% of patients were women and 62.6% were in functional class III. Mean time of follow-up was 55.5 (SD 26.1) weeks. Women showed a significantly better response in cardiac index (mean difference [MD], 0.10L/min/m2; 95% confidence interval [CI], 0.04-0.16; I2=0%; P=0.001). Alternatively, the reduction of pulmonary vascular resistances was significantly higher for men than for women (MD, 161.17dynscm-5; 95% CI, 67.99-254.35; I2=0%; P=0.0007). CONCLUSIONS: Women and men might show different hemodynamic responses to riociguat or BPA for CTEPH.

Usefulness of the National Early Warning Score for Risk Stratification of Stable Patients With Acute Symptomatic Pulmonary Embolism.

OBJECTIVES: The aim of this study was to assess the performance of the National Early Warning Score 2 (NEWS2) in predicting a short-term complicated outcome in stable patients with acute symptomatic pulmonary embolism (PE). We also studied the ability of the NEWS2 score compared with the simplified Pulmonary Embolism Severity Index (sPESI) for identifying low-risk patients with acute PE. METHODS: We performed a retrospective analysis of a prospective cohort composed of 848 patients with acute PE. The NEWS2 and the sPESI were calculated for each patient according to different clinical variables. We assessed the predictive accuracy of these scores for a 30-day complicated outcome using the C statistic, which was obtained by logistic regression models and ROC curves. We also assessed the test and performance characteristics of the low-risk versus high-risk categories of each prediction rule. RESULTS: Overall, 63 out of 848 patients died (7.4%; 95% confidence interval, 5.7%-9.2%) during the first month of follow-up. Both scores showed a similarly poor predictive value for 30-day complicated outcome (C statistic, 0.68 and 0.62). The sPESI classified fewer patients as low-risk (36.9% versus 44.5%; P<0.01). Compared with the NEWS2 score, the sPESI showed significantly higher sensitivity (92.1% versus 66.7%) and a better negative predictive value (98.4% versus 94.4%). CONCLUSION: Both scores provide similar information for stratifying the risk of a complicated outcome in stable patients with PE. The sPESI identified low-risk patients with PE better than the NEWS2 score.

Feasibility of a screening algorithm for chronic thromboembolic pulmonary hypertension: The OSIRIS study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel to pulmonary embolism (PE) whose incidence varies according to different published studies. We have carried out this study to determine its incidence within 2 years after index pulmonary embolism and to study limitations to an early diagnosis. MATERIAL AND METHODS: OSIRIS is a multicentre, longitudinal cohort study. Patients were followed for 3, 6, 12, and 24 months after pulmonary embolism using a structured three-step algorithm. A physician-centered questionnaire at least one positive response in a screening proceeded to the second step, transthoracic echocardiography. The third step consisted of ventilation/perfusion lung scintigraphy and right heart catheterisation. A transthoracic echocardiography was performed in patients without positive response in the screening questionnaire after 2 years. CTEPH diagnosis required haemodynamic confirmation by right heart catheterisation and mismatched perfusion defects on lung scintigraphy. RESULTS: A total of 1191 patients were enrolled in 18 Spanish hospitals. Cumulative CTEPH incidence after 2-years PE was: 2.49 % (95 % CI: 1.68-3.56) and the incidence rate of CTEPH was 1.1 cases per 1000 person-months (95 % CI: 0.725; 1.60). The CTEPH algorithm presented a lack of adherence of 29 %; patient and physician preferences posed barriers to the triage algorithm The screening questionnaire, in patients who completed the follow-up, shows a specificity of 91.3 % (89.0-93.2 %) and negative predictive value of 99.4 % (98.4-99.8 %).. CONCLUSIONS: OSIRIS provides practiced clinical based data on the chronic thromboembolic pulmonary hypertension incidence and identified barriers to the implementation of a 3-step triage algorithm for its detection. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03134898.

Refinement of a modified simplified Pulmonary Embolism Severity Index for elderly patients with acute pulmonary embolism.

OBJECTIVE: To evaluate the utility of a modified (i.e., without the variable "Age >80 years") simplified Pulmonary Embolism Severity Index (sPESI) in elderly patients with acute symptomatic pulmonary embolism (PE), and to derive and validate a refined version of the sPESI for identification of elderly patients at low risk of adverse events. METHODS: The study included normotensive patients aged >80 years with acute PE enrolled in the RIETE registry. We used multivariable logistic regression analysis to create a new risk score to predict 30-day all-cause mortality. We externally validated the new risk score in elderly patients from the COMMAND VTE registry. RESULTS: Multivariable logistic regression identified four predictors for mortality: high-risk sPESI, immobilization, coexisting deep vein thrombosis (DVT), and plasma creatinine >2 mg/dL. In the RIETE derivation cohort, the new model classified fewer patients as low risk (4.0% [401/10,106]) compared to the modified sPESI (35% [3522/10,106]). Low-risk patients based on the new model had a lower 30-day mortality than those based on the modified sPESI (1.2% [95% CI, 0.4-2.9%] versus 4.7% [95% CI, 4.0-5.4%]). In the COMMAND VTE validation cohort, 1.5% (3/206) of patients were classified as having low risk of death according to the new model, and the overall 30-day mortality of this group was 0% (95% CI, 0-71%), compared to 5.9% (95% CI, 3.1-10.1%) in the high-risk group. CONCLUSIONS: For predicting short-term mortality among elderly patients with acute PE, this study suggests that the new model has a substantially higher sensitivity than the modified sPESI. A minority of these patients might benefit from safe outpatient therapy of their disease.

Implications of Abnormal Troponin Levels With Normal Right Ventricular Function in Normotensive Patients With Acute Pulmonary Embolism.

Among patients with pulmonary embolism (PE), various permutations of normal or abnormal cardiac troponin results and normal or abnormal echocardiographic right ventricular function are encountered in clinical practice. We aimed to explore whether there is a true gradient of risk based on troponin and echocardiographic results. This study included normotensive patients with PE from the PROgnosTic valuE of CT scan in hemodynamically stable patients with acute symptomatic pulmonary embolism (PROTECT) study. Patients were categorized as having -Troponin/-Echo, -Troponin/+Echo, +Troponin/-Echo, and +Troponin/+Echo. The primary outcome was 30-day "complicated course," including death from any cause, hemodynamic collapse, or recurrent PE. Secondary outcomes included individual adverse event rates. Of the 834 patients who had echocardiographic and troponin results, 569 patients (68%) had -Troponin/-Echo, 126 patients (15%) had -Troponin/+Echo, 74 patients (8.9%) had +Troponin/-Echo, and 65 patients (7.8%) had +Troponin/+Echo. The incidence of 30-day complicated course was 4.6% in patients with -Troponin/-Echo, 11.9% in patients with -Troponin/+Echo, 13.5% in patients with +Troponin/-Echo, and 16.9% in patients with +Troponin/+Echo (P for trend <0.001). In the subgroup of patients with a high-risk sPESI (i.e., intermediate-risk according to the ESC guidelines) (n = 527), the incidence of 30-day complicated course was 14.9% in patients with -Troponin/+Echo, 18.5% in patients with +Troponin/-Echo, and 17.5% in patients with +Troponin/+Echo (P for trend <0.01). In patiens with PE, there seems to be a risk gradient based on troponin and echocardiographic results. This study did not detect a significant risk difference in those with +Troponin/-Echo compared with -Troponin/+Echo.

Intermediate-High Risk Pulmonary Embolism.

Limited information exists about the prevalence, management, and outcomes of intermediate-high risk patients with acute pulmonary embolism (PE). In a prospective cohort study, we evaluated consecutive patients with intermediate-high risk PE at a large, tertiary, academic medical center between January 1, 2015 and March 31, 2019. Adjudicated outcomes included PE-related mortality and a complicated course through 30 days after initiation of PE treatment. Repeat systolic blood pressure (SBP), heart rate (HR), brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) measurements, and echocardiography were performed within 48 hours after diagnosis. Among 1,015 normotensive patients with acute PE, 97 (9.6%) had intermediate-high risk PE. A 30-day complicated course and 30-day PE-related mortality occurred in 23 (24%) and 7 patients (7.2%) with intermediate-high risk PE. Seventeen (18%) intermediate-high risk patients received reperfusion therapy. Within 48 hours after initiation of anticoagulation, normalization of SBP, HR, cTnI, BNP, and echocardiography occurred in 82, 86, 78, 72, and 33% of survivors with intermediate-high risk PE who did not receive immediate thrombolysis. A complicated course between day 2 and day 30 after PE diagnosis for the patients who normalized SBP, HR, cTnI, BNP, and echocardiography measured at 48 hours occurred in 2.9, 1.4, 4.5, 3.3, and 14.3%, respectively. Intermediate-high risk PE occurs in approximately one-tenth of patients with acute symptomatic PE, and is associated with high morbidity and mortality. Normalization of HR 48 hours after diagnosis might identify a group of patients with a very low risk of deterioration during the first month of follow-up.

Pulmonary embolism severity assessment and prognostication.

For patients who have acute symptomatic pulmonary embolism (PE), risk of short-term death and adverse outcomes should drive the initial treatment decisions. Practice guidelines recommend that patients who have a high-risk of PE-related death and adverse outcomes, determined by the presence of haemodynamic instability (i.e., shock or hypotension), should receive systemically administered thrombolytic therapy. Intermediate-high risk patients might benefit from close observation, and some should undergo escalation of therapy beyond standard anticoagulation, particularly if haemodynamic deterioration occurs. Low-risk for adverse outcomes should lead to early hospital discharge or full treatment at home. Validated prognostic tools (i.e., clinical prognostic scoring systems, imaging studies, and cardiac laboratory biomarkers) assist with risk classification of patients who have acute symptomatic PE.

Diclofenac for reversal of right ventricular dysfunction in acute normotensive pulmonary embolism: A pilot study.

BACKGROUND: The inflammatory response associated with acute pulmonary embolism (PE) contributes to the development of right ventricular (RV) dysfunction. Nonsteroidal anti-inflammatory drugs (NSAIDs) may facilitate the reversal of PE-associated RV dysfunction. METHODS: We randomly assigned normotensive patients who had acute PE associated with echocardiographic RV dysfunction and normal systemic blood pressure to receive intravenous (IV) diclofenac (two doses of 75mg in the first 24h after diagnosis) or IV placebo. All patients received standard anticoagulation with subcutaneous low-molecular-weight heparin (LMWH) and an oral vitamin K antagonist. RV dysfunction was defined by the presence of, at least, two of the following criteria: i) RV diastolic diameter>30mm in the parasternal window; ii) RV diameter>left ventricle diameter in the apical or subcostal space; iii) RV free wall hypokinesis; and iv) estimated pulmonary artery systolic pressure>30mmHg. Persistence of RV dysfunction at 48h and 7days after randomization were the primary and secondary efficacy outcomes, respectively. The primary safety outcome was major bleeding within 7days after randomization. RESULTS: Of the 34 patients randomly assigned to diclofenac or placebo, the intention-to-treat analysis showed persistent RV dysfunction at 48h in 59% (95% confidence interval [CI], 33-82%) of the diclofenac group and in 76% (95% CI, 50-93%) of the placebo group (difference in risk [diclofenac minus standard anticoagulation], -17 percentage points; 95% CI, -47 to 17). Similar proportions (35%) of patients in the diclofenac and placebo groups had persistent RV dysfunction at 7days. Major bleeding occurred in none of patients in the diclofenac group and in 5.9% (95% CI, 0.2-29%) of patient in the placebo group. CONCLUSIONS: Due to slow recruitment, our study is inconclusive as to a potential benefit of diclofenac over placebo to reverse RV dysfunction in normotensive patients with acute PE. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01590342.

Higher Adherence to Treatment With Low-Molecular-Weight-Heparin Nadroparin Than Enoxaparin Because of Side Effects in Cancer-Associated Venous Thromboembolism.

Current guidelines recommend low-molecular-weight-heparins (LMWH) monotherapy for 3 to 6 months as first-line treatment for cancer-associated venous thromboembolism (VTE). In clinical practice, enoxaparin and nadroparin are common agents used. However, differences in therapy adherence between these LMWHs have never been reported. Therefore, our aim was to compare adherence to enoxaparin and nadroparin in patients with cancer-associated VTE. Consecutive patients with active cancer and objectively confirmed VTE, treated at a Dutch or a Spanish hospital, were followed during LMWH therapy with a maximum of 180 days. Cumulative incidences of discontinuation of both LMWHs were estimated and compared according to the Kaplan-Meier method, applying a competing risk analysis to correct for mortality. A total of 366 patients were analyzed during LMWH treatment, of whom 284 patients (78%) were treated with enoxaparin and 82 (22%) with nadroparin. The cumulative incidence of discontinuation of enoxaparin and nadroparin treatment because of side effects was 30% (95% confidence interval [CI] 24-36) and 8.8% (95% CI 1.1-15), respectively. Competing risk analysis revealed a higher number of patients discontinuing enoxaparin due to side effects (adjusted hazard ratio [HR]: 2.8; 95% CI 1.06-7.2). Pain at the injection site was the most common reason of discontinuation in patients using enoxaparin, occurring in 32 patients, while it occurred in 1 patient using nadroparin (adjusted HR: 4.0; 95% CI 0.52-31). This analysis reveals that enoxaparin was associated with a higher risk of discontinuation because of side effects compared to nadroparin. However, given the nature of the patient groups, these findings should be followed by future studies.

Assessment of coexisting deep vein thrombosis for risk stratification of acute pulmonary embolism.

BACKGROUND: In patients with acute pulmonary embolism (PE), studies have shown an association between coexisting deep vein thrombosis (DVT) and short-term prognosis. It is not known whether complete compression ultrasound testing (CCUS) improves the risk stratification of their disease beyond the recommended prognostic models. METHODS: We included patients with normotensive acute symptomatic PE and prognosticated them with the European Society of Cardiology (ESC) risk model for PE. Subsequently, we determined the prognostic significance of coexisting DVT in patients with various ESC risk categories. The primary endpoint was a complicated course after the diagnosis of PE, defined as death from any cause, haemodynamic collapse, or adjudicated recurrent PE. RESULTS: According to the ESC model, 37% of patients were low-risk, 56% were intermediate-low risk, and 6.7% were intermediate-high risk. CCUS demonstrated coexisting DVT in 375 (44%) patients. Among the 313 patients with low-risk PE, coexisting DVT (46%) did not show a significant increased risk of complicated course (2.8%; 95% confidence interval [CI], 0.8%-7.0%), compared with those without DVT (0.6%; 95% CI, 0%-3.2%), (P = 0.18). Of the 478 patients with intermediate-low risk PE, a complicated course was 14% and 6.8% for those with and without DVT, respectively (P = 0.01). Of the 57 patients that had intermediate-high risk PE, a complicated course occurred in 17% and 18% for those with and without DVT, respectively (P = 1.0). CONCLUSIONS: In normotensive patients with PE, testing for coexisting DVT might improve risk stratification of patients at intermediate-low risk for short-term complications.