INTRODUCTION: Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined.
METHODS: In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) 'post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV.
RESULTS: Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up.
CONCLUSIONS: CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae.
OBJECTIVES: To investigate the efficacy and safety of initial thrombolysis by recombinant tissue-type plasminogen activator (rt-PA) in compared with anticoagulant therapy in patients with acute intermediate-risk pulmonary embolism (PE). Methods: Sixty-six patients with acute intermediate-risk PE were randomly assigned to receive rt-PA or LMWH between June 2014 and June 2017 in our department. We obtained information regarding the difference in the right ventricle/left ventricle (RV/LV) ratio, pulmonary artery systolic pressure (PASP), clinical symptoms improvement, PE-related mortality, hemodynamic decompensation, recurrent PE, and major and minor bleeding. Results: In the rt-PA group, the mean PASP was reduced from 52.0±12.2 at baseline to 34.8±9.4 (p less than 0.001) and the mean RV/LV ratio was reduced from 1.26±0.22 at baseline to 0.96±0.18 (p less than 0.001) at 24 hours. In the LMWH group, the mean PASP was 53.4±12.8 at baseline and 48.5±11.9 at 24 hours (p=0.11), and the mean RV/LV ratio was 1.22±0.19 at baseline and 1.17±0.21 at 24 hours (p=0.31). In comparison with the LMWH group, there was a significant reduction in PASP and an improvement in the symptom severity in the rt-PA group. At 90 days, there was no difference in mortality, recurrent venous thromboembolism and major bleeding as a safety outcome, but increased minor bleeding and decreased hemodynamic decompensation occurred in the rt-PA group. Conclusions: In patients with acute intermediate-risk PE, low dose thrombolytic therapy is considered safe and effective, it can be recommended as an alternative option in clinical treatment.
Background and aim of the study The aim of this study was to assess the value of streptokinase in patients with submassive pulmonary embolism (PE) due to unavailability of tissue plasminogen activator in our locality due to limited income sources. Patients and methods A prospective randomized controlled trial was conducted on a total number of 52 patients with a confirmed diagnosis of submassive PE confirmed by computed tomographic pulmonary angiography were further investigated by echocardiography and cardiac biomarkers after ethical approval from the IRB and confirmed written consent from the patients or first-degree relative. The study was conducted between January 2017 and December 2017, at the Chest Department, Mansoura University Hospitals, and the Cardiology Department, Specialized Internal Medicine Hospital, Faculty of Medicine, Mansoura University. Results Fifty-two patients who were diagnosed as having submassive PE were enrolled; 24 patients were randomized to the thrombolytic group (TG) and 28 to the anticoagulant group (AG) by simple randomization through opening a closed envelope. The two groups were compared as regards demographic data, pulmonary artery systolic pressure (PASP), presence of comorbidities (diabetes mellitus) and presence of malignancy or concomitant deep venous thrombosis as risk factors, and the incidence of unprovoked PE without any statistically significant results.The PASP measured 72 h after therapy in the TG was improved with statistically significant difference when compared with that measured before starting therapy (P<0.001). In contrast, there was no statistically significant difference in the changes in PASP before and after therapy in the AG (P=0.06). Thereafter, PASP measured 72 h after therapy in TG was lower, with statistically significant difference than that measured 72 hours after therapy in AG (P<0.001). As regards the effect of therapy in TG, 12 of 50 still had pulmonary hypertension in the follow-up echocardiography carried out 72 h after starting therapy versus 24 of 28 in AG with statistically significant difference (P=0.003). Moreover, hospital stay in TG was lower than that of AG (6.5±1.5 vs. 7.6±1.66, P=0.013). No bleeding was detected in both groups. Conclusion Thrombolytic therapy should be considered over anticoagulation as first-line management in submassive PE causing right ventricular dysfunction without hypotension. Clinical implications Early identification of submassive PE and start of thrombolytic therapy after exclusion of bleeding risk in the patient for thrombolysis can improve outcome and decrease hospital stay.
BACKGROUND: The long-term effect of thrombolytic treatment of pulmonary embolism (PE) is unknown.
OBJECTIVES: This study investigated the long-term prognosis of patients with intermediate-risk PE and the effect of thrombolytic treatment on the persistence of symptoms or the development of late complications.
METHODS: The PEITHO (Pulmonary Embolism Thrombolysis) trial was a randomized (1:1) comparison of thrombolysis with tenecteplase versus placebo in normotensive patients with acute PE, right ventricular (RV) dysfunction on imaging, and a positive cardiac troponin test result. Both treatment arms received standard anticoagulation. Long-term follow-up was included in the third protocol amendment; 28 sites randomizing 709 of the 1,006 patients participated.
RESULTS: Long-term (median 37.8 months) survival was assessed in 353 of 359 (98.3%) patients in the thrombolysis arm and in 343 of 350 (98.0%) in the placebo arm. Overall mortality rates were 20.3% and 18.0%, respectively (p = 0.43). Between day 30 and long-term follow-up, 65 deaths occurred in the thrombolysis arm and 53 occurred in the placebo arm. At follow-up examination of survivors, persistent dyspnea (mostly mild) or functional limitation was reported by 36.0% versus 30.1% of the patients (p = 0.23). Echocardiography (performed in 144 and 146 patients randomized to thrombolysis and placebo, respectively) did not reveal significant differences in residual pulmonary hypertension or RV dysfunction. Chronic thromboembolic pulmonary hypertension (CTEPH) was confirmed in 4 (2.1%) versus 6 (3.2%) cases (p = 0.79).
CONCLUSIONS: Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients. (Pulmonary Embolism Thrombolysis study [PEITHO]; NCT00639743).
BACKGROUND: Thrombolysis in acute submassive pulmonary embolism (PE) remains controversial. So we studied impact of thrombolytic therapy in acute submassive PE in terms of mortality, hemodynamic status, improvement in right ventricular function, and safety in terms of major and minor bleeding.
METHOD: A single-center, prospective, randomized study of 86 patients was conducted at LPS Institute of Cardiology, G.S.V.M. Medical College, Kanpur, India. Patients received thrombolysis (single bolus of tenecteplase) with unfractionated heparin (UFH, group I) or placebo with UFH (group II).
RESULT: Mean age of patients was 54.35 ± 12.8 years with male dominance (M:F = 70%:30%). Smoking was the most common risk factor seen in 29% of all patients, followed by recent history of immobilization (25%), history of surgery or major trauma within past 1 month (15%), dyslipidemia (10%) and diabetes mellitus (10%). Dyspnea was the most common symptom in 80% of all patients, followed by chest pain in 55% and syncope in 6%. Primary efficacy outcome occurred significantly better in group I vs. group II (4.5% vs. 20%; P = 0.04), and significant difference was also found in hemodynamic decompensation (4.5% vs. 20%; P = 0.04), the fall in mean pulmonary artery systolic pressure (PASP) (28.8% vs. 22.5%; P = 0.03), improvement in right ventricular (RV) function (70% vs. 40%; P = 0.001) and mean hospital stay (8.1 ± 2.5 vs. 11.1 ± 2.14 days; P = 0.001). There was no difference in mortality and major bleeding as safety outcome but increased minor bleeding occurred in group I patients (16% vs. 12%; P = 0.04).
CONCLUSION: Patients with acute submassive PE do not derive overall mortality benefit, recurrent PE and rehospitalization with thrombolytic therapy but had improved clinical outcome in form of decrease in hemodynamic decompensation, mean hospital stay, PASP and improvement of RV function with similar risk of major bleed but at cost of increased minor bleeding.
: Previous studies have associated biomarkers indicative of acute inflammation with pulmonary embolism, which may amplify coagulation, inhibit fibrinolysis and increase risk of venous thromboembolism (VTE) recurrence. The aim of this study was to measure inflammatory and hemostatic biomarkers in acute submassive pulmonary embolism at diagnosis and 3-month follow-up and to test the impact of treatment with fibrinolysis. Secondary analysis of a multicenter, double-blinded, randomized controlled trial including patients with submassive pulmonary embolism. Blood samples were obtained within 24 h of diagnosis and prior to bolus-dose tenecteplase (TNK) or placebo; all patients received standard anticoagulation and blood was redrawn 3 months later. Plasma concentrations of inflammatory [Interleukin 6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO)] and hemostatic [plasminogen activator inhibitor-1 (PAI-1), fibrinogen, thrombin-activatable fibrinolysis inhibitor and D-dimer] biomarkers were quantified. The median values of the biomarkers of inflammation (IL-6, CRP, MPO) were all significantly decreased at 3-month follow-up, ranging from a 60 to 91% reduction over this time period. Concentrations of PAI-1 and fibrinogen did not change significantly. D-dimer concentration at 3-month follow-up was lower in patients treated with fibrinolysis vs. placebo and appeared to have a trend toward significance (placebo 310 vs. TNK 220 ng/ml, P = 0.051). Acute pulmonary embolism causes marked but transient inflammation, as demonstrated by the significant elevation in the inflammatory biomarkers at diagnosis, followed by their reduction in more than 80% of patients at 3-month follow-up.
IMPORTANCE: Low-molecular-weight heparin is recommended over warfarin for the treatment of acute venous thromboembolism (VTE) in patients with active cancer largely based on results of a single, large trial.
OBJECTIVE: To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute, symptomatic VTE in patients with active cancer.
DESIGN, SETTINGS, AND PARTICIPANTS: A randomized, open-label study with blinded central adjudication of study outcomes enrolled patients in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013. Adult patients with active cancer (defined as histologic diagnosis of cancer and receiving anticancer therapy or diagnosed with, or received such therapy, within the previous 6 months) and objectively documented proximal deep vein thrombosis (DVT) or pulmonary embolism, with a life expectancy greater than 6 months and without contraindications for anticoagulation, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data.
INTERVENTIONS: Tinzaparin (175 IU/kg) once daily for 6 months vs conventional therapy with tinzaparin (175 IU/kg) once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio within the therapeutic range (2.0-3.0) for 6 months.
MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was a composite of centrally adjudicated recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and overall mortality.
RESULTS: Nine hundred patients were randomized and included in intention-to-treat efficacy and safety analyses. Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89 [95% CI, 0.40-1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin; HR, 1.08 [95% CI, 0.85-1.36]; P = .54). A significant reduction in clinically relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004).
CONCLUSIONS AND RELEVANCE: Among patients with active cancer and acute symptomatic VTE, the use of full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did not significantly reduce the composite measure of recurrent VTE and was not associated with reductions in overall mortality or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding. Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130025.
BACKGROUND: In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients.
METHODS AND RESULTS: Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (P=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (P<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group; P=0.61), and no recurrent venous thromboembolism.
CONCLUSIONS: In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166997.
BACKGROUND: The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial.
METHODS: In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization.
RESULTS: Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42).
CONCLUSIONS: In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).
Symptoms and functional limitation are frequently reported by survivors of acute pulmonary embolism (PE). However, current guidelines provide no specific recommendations on which patients should be followed after acute PE, when follow-up should be performed, and which tests it should include. Definition and classification of late PE sequelae are evolving, and their predictors remain to be determined.
METHODS:
In a post hoc analysis of the Pulmonary Embolism Thrombolysis (PEITHO) trial, we focused on 219 survivors of acute intermediate-risk PE with clinical and echocardiographic follow-up 6 months after randomisation as well as over the long term (median, 3 years after acute PE). The primary outcome was a composite of (1) confirmed chronic thromboembolic pulmonary hypertension (CTEPH) or (2) 'post-PE impairment' (PPEI), defined by echocardiographic findings indicating an intermediate or high probability of pulmonary hypertension along with New York Heart Association functional class II-IV.
RESULTS:
Confirmed CTEPH or PPEI occurred in 29 (13.2%) patients, (6 with CTEPH and 23 with PPEI). A history of chronic heart failure at baseline and incomplete or absent recovery of echocardiographic parameters at 6 months predicted CTEPH or PPEI at long-term follow-up.
CONCLUSIONS:
CTEPH or PPEI occurs in almost one out of seven patients after acute intermediate-risk PE. Six-month echocardiographic follow-up may be useful for timely detection of late sequelae.
