Effects of pulmonary rehabilitation on cardiac magnetic resonance parameters in patients with persistent dyspnea following pulmonary embolism.

Background: Persistent dyspnea and reduced exercise capacity is common in pulmonary embolism (PE) survivors. Although improved right ventricular function after pulmonary rehabilitation has been demonstrated in chronic thromboembolic pulmonary hypertension, it is still unknown whether a similar effect also occurs in other patients with dyspnea after pulmonary embolism. Purpose: The aim of this study was to explore potential effects of a pulmonary rehabilitation program on cardiac structure and function as assessed with cardiac magnetic resonance (CMR). Material and methods: Twenty-six PE survivors with persistent dyspnea were included. Right and left ventricular assessment with CMR was performed before and after an eight-week pulmonary rehabilitation program. Results: Dyspnea as measured by the Shortness of Breath Questionnaire improved significantly after rehabilitation: 15 (IQR: 7-31) versus 8 (IQR: 3-17). Absolute right ventricular global longitudinal strain by CMR was reduced from 19% to 18% (95% CI of difference: 0-3 percent points), and absolute RV lateral strain from 26% to 24% (95% CI of difference: 1-4 percent points). Right ventricular mass was reduced after rehabilitation from 49 g to 44 g (95% CI of difference: 2-8 g). Conclusion: Although there was a substantial improvement in dyspnea after rehabilitation, we found only a minor reduction in absolute right ventricular longitudinal strain and right ventricular mass. No other CMR parameter changed. We therefore suggest that rehabilitation effect of in this patient group was not primarily mediated by cardiac adaptions.

Measuring functional limitations after venous thromboembolism: Optimization of the Post-VTE Functional Status (PVFS) Scale.

INTRODUCTION: We recently proposed a scale for assessment of patient-relevant functional limitations following an episode of venous thromboembolism (VTE). Further development of this post-VTE functional status (PVFS) scale is still needed. METHODS: Guided by the input of VTE experts and patients, we refined the PVFS scale and its accompanying manual, and attempted to acquire broad consensus on its use. RESULTS: A Delphi analysis was performed involving 53 international VTE experts with diverse scientific and clinical backgrounds. In this process, the number of scale grades of the originally proposed PVFS scale was reduced and descriptions of the grades were improved. After these changes, a consensus was reached on the number/definitions of the grades, and method/timing of the scale assessment. The relevance and potential impact of the scale was confirmed in three focus groups totaling 18 VTE patients, who suggested additional changes to the manual, but not to the scale itself. Using the improved manual, the κ-statistics between PVFS scale self-reporting and its assessment via the structured interview was 0.75 (95%CI 0.58-1.0), and 1.0 (95%CI 0.83-1.0) between independent raters of the recorded interview of 16 focus groups members. CONCLUSION: We improved the PVFS scale and demonstrated broad consensus on its relevance, optimal grades, and methods of assessing among international VTE experts and patients. The interobserver agreement of scale grade assignment was shown to be good-to-excellent. The PVFS scale may become an important outcome measure of functional impairment for quality of patient care and in future VTE trials.

Safety of D-dimer testing as a stand-alone test for the exclusion of deep vein thrombosis as compared with other strategies.

Essentials The aim of deep vein thrombosis (DVT) diagnostic work-up is to maximize both safety and efficiency. We explored whether D-dimer is safe and efficient as a stand-alone test to exclude DVT. Our findings suggest it is a safe, efficient and simplified diagnostic strategy. The safety of age-adjusted D-dimer as a stand-alone test requires further investigation. SUMMARY: Background Several strategies for safely excluding deep vein thrombosis (DVT) while limiting the number of imaging tests have been explored. Objectives To determine whether D-dimer testing could safely and efficiently exclude DVT as a stand-alone test, and evaluate its performance as compared with strategies that incorporate the Wells score and age-adjusted D-dimer. Patients/Methods We included consecutive outpatients referred with suspected DVT to the Emergency Department at Østfold Hospital, Norway. STA-Liatest D-Di PLUS D-dimer was analyzed for all patients. Patients with a D-dimer level of ≥ 0.5 µg mL-1 were referred for compression ultrasonography (CUS). In patients with a D-dimer level of < 0.5 µg mL-1 , no further testing was performed and anticoagulation was withheld. Patients were followed for 3 months for venous thromboembolism (VTE). Results Of the 913 included patients, 298 (33%) had a negative D-dimer result. One hundred and seventy-three patients (18.9%) were diagnosed with DVT at baseline. One of 298 patients had DVT despite having a negative D-dimer result, resulting in a failure rate of 0.3% (95% confidence interval [CI] 0.1-1.9%). Adding the modified Wells score would have yielded a failure rate of 0.0% (95% CI 0.0-1.8%) while necessitating 87 more CUS examinations. Age-adjusted D-dimer as a stand-alone test would have necessitated 80 fewer CUS examinations than fixed D-dimer as a stand-alone test, at the cost of a failure rate of 1.6% (95% CI 0.7-3.4%). Conclusions This outcome study shows that a negative high-sensitivity D-dimer result safely excludes DVT in an outpatient population, and necessitates fewer CUS than if used in combination with Wells score. The safety of stand-alone age-adjusted D-dimer needs further assessment in prospective outcome studies.

Rivaroxaban versus warfarin for the prevention of post-thrombotic syndrome.

INTRODUCTION: Despite treatment of acute deep vein thrombosis (DVT) with low molecular weight heparin and warfarin, up to 50% of patients develop post-thrombotic syndrome (PTS). Our aims were to assess whether treatment of DVT with rivaroxaban would reduce the rate of subsequent PTS and improve health-related quality of life (HRQoL) as compared to conventional anticoagulation with low molecular weight heparin (LMWH)/warfarin. MATERIALS AND METHODS: Consecutive patients with an objectively confirmed DVT diagnosed between 2011 and 2014 and treated with either rivaroxaban or warfarin were included in this study 24 (±6) months after DVT. PTS was assessed using the Patient Reported Villalta scale. HRQoL was assessed using the EQ-5D-3L and VEINES-QOL/Sym questionnaires. RESULTS: Total 309 patients were included, 161 (52%) treated with rivaroxaban and 148 (48%) with warfarin. Rivaroxaban-treated patients had a lower rate of PTS (45%: 95% confidence interval [CI] 37 to 52) compared to those treated with warfarin (59%: 95% CI 51 to 66, absolute risk difference 14%: 95% CI 3 to 25, odds ratio (OR) 0.6, P = .01). The adjusted OR for development of PTS was 0.5 (95% CI: 0.3 to 0.8, P = .01) in patients treated with rivaroxaban. HRQoL was significantly better in the rivaroxaban-treated patients. HRQoL measured by EQ-VAS (P = .002) and VEINES-QOL/Sym (P = .005/P = .003) remained significantly better after adjustment. CONCLUSIONS: Patients treated with rivaroxaban had lower rate of PTS and better HRQoL after DVT compared to patients treated with warfarin. However, these results should be interpreted with caution due to the limitation imposed by study design.

JAK2 V617F mutation can be reliably detected in serum using droplet digital PCR.

INTRODUCTION: Detection of the JAK2 V617F mutation is a key step in the diagnosis of myeloproliferative neoplasms (MPN). Sensitive real-time quantitative PCR (qPCR) detection on peripheral blood (PB) is the most widely used method. The main objective of this study was to determine whether serum, the most common material available in archival biobanks, is a good liquid biopsy for detecting and quantifying the JAK2 V617F mutation using droplet digital PCR (ddPCR). METHODS: Paired PB and serum samples from 66 patients with MPN were used. Serum samples were frozen at -25°C before analysis. DNA was extracted from 200 µL PB and 400 µL serum, and ddPCR analysis was performed. RESULTS: Among the 47 patients with detectable mutation in their PB samples, the overall sensitivity for the detection of JAK2 mutation in serum was of 96% (45 of 47); V617F was detected in all cases where mutation load was above 1%. Our results showed very strong correlation between PB and serum (Spearman r: 0.989, P < .0001). Significantly higher allele burden was detected in serum compared to PB (Wilcoxon signed ranks test, Z = -5.672, P < .0001). CONCLUSION: In our study, JAK2 V617F mutation load as low as 1% was reliably detected in serum using ddPCR.

Decreased plasma cytokines are associated with low platelet counts in aplastic anemia and immune thrombocytopenic purpura.

BACKGROUND: We previously found plasma levels of CD40 ligand (CD40L), chemokine (C-X-C motif) ligand 5 (CXCL5), chemokine (C-C motif) ligand 5 (CCL5) and epidermal growth factor (EGF) to be low in aplastic anemia (AA) patients and to be correlated with platelet count. OBJECTIVES: To study the association of CD40L, CXCL5, CCL5 and EGF with platelets. METHODS: We measured cytokines in the plasma of immune thrombocytopenic purpura (ITP) and AA patients using the Luminex assay and confirmed the results in a mouse model and in vitro experiments. RESULTS: Both ITP and AA showed similarly low levels of CD40L, CXCL5, CCL5 and EGF, compared with healthy controls. In ITP, levels of these proteins were significantly greater in patients with higher platelet counts than in those with lower platelet counts. In a murine thrombocytopenia model, levels of CD40L, CXCL5, CCL5 and EGF decreased with platelet count after immune-mediated destruction, while the cytokine levels increased when the platelet count recovered. In vitro, concentrations of these cytokines in the supernatants of platelet suspensions were proportional to platelet numbers, and levels in sera prepared by simple blood coagulation were equivalent to those in platelet-rich plasma-converted sera. mRNA expression for CXCL5, CCL5 and EGF was higher in platelets than in megakaryocytes, peripheral blood mononuclear cells, granulocytes and non-megakaryocytic bone marrow cells. CONCLUSIONS: Plasma CD40L, CXCL5, CCL5 and EGF are mainly platelet-derived, suggesting a role of platelets in immune responses and inflammation. Measurement of CD40L, CXCL5, CCL5 and EGF in human blood allowed testable inferences concerning physiology and pathophysiology in quantitative platelet disorders.

Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.

BACKGROUND: Approximately one in four patients with acute proximal deep vein thrombosis (DVT) given anticoagulation and compression therapy develop post-thrombotic syndrome (PTS). Accelerated removal of thrombus by thrombolytic agents may increase patency and prevent PTS. OBJECTIVES: To assess short-term efficacy of additional catheter-directed thrombolysis (CDT) compared with standard treatment alone. PATIENTS AND METHODS: Open, multicenter, randomized, controlled trial. Patients (18-75 years) with iliofemoral DVT and symptoms < 21 days were randomized to receive additional CDT or standard treatment alone. After 6 months, iliofemoral patency was investigated using duplex ultrasound and air-plethysmography assessed by an investigator blinded to previous treatment. RESULTS: One hundred and three patients (64 men, mean age 52 years) were allocated additional CDT (n = 50) or standard treatment alone (n = 53). After CDT, grade III (complete) lysis was achieved in 24 and grade II (50%-90%) lysis in 20 patients. One patient suffered major bleeding and two had clinically relevant bleeding related to the CDT procedure. After 6 months, iliofemoral patency was found in 32 (64.0%) in the CDT group vs. 19 (35.8%) controls, corresponding to an absolute risk reduction (RR) of 28.2% (95% CI: 9.7%-46.7%; P = 0.004). Venous obstruction was found in 10 (20.0%) in the CDT group vs. 26 (49.1%) controls; absolute RR 29.1% (95% CI: 20.0%-38.0%; P = 0.004). Femoral venous insufficiency did not differ between the two groups. CONCLUSIONS: After 6 months, additional CDT increased iliofemoral patency from 36% to 64%. The ongoing long-term follow-up of this study will document whether patency is related to improved functional outcome.

Multidetector computed tomography (MDCT) in the diagnosis of pulmonary embolism: interobserver agreement among radiologists with varied levels of experience.

PURPOSE: To assess the interobserver variability of radiologists with varied levels of experience in the interpretation of multidetector computed tomography (MDCT) pulmonary angiographies. MATERIAL AND METHODS: Review of CT pulmonary angiographies performed on patients included in a diagnostic study evaluating a decision-based algorithm for diagnosing pulmonary embolism (PE). Five radiologists, three board-certified general radiologists and two radiology trainees with 2 years' experience, participated in the study. RESULTS: According to the consensus reading, PE was present in 91 (31%) and absent in 194 (67%) patients, while in five patients (1.7%) the interpretations were regarded as equivocal. The per-patient agreement on the diagnosis of PE achieved by each of the four readers compared to the consensus reading was very good (kappa range 0.85-0.92), but peripheral emboli were missed in four to six patients by three of four observers. The agreement on the most proximal level of PE (per-proximal level) assessed by mean kappa value was 0.83 (kappa range 0.68-0.91) for the detection of proximal emboli, 0.61 for segmental emboli (kappa range 0.40-0.80), and 0.38 for emboli in the subsegmental vessels (kappa range 0.0-0.89). CONCLUSION: The overall agreement on the diagnosis of PE by MDCT for general radiologists and radiology trainees is very good, and we therefore believe that the initial management of patients with suspected PE could be based on the preliminary assessment performed by on-call radiologists with 2 years of experience.

The association between the proximal extension of the clot and the severity of pulmonary embolism (PE): a proposal for a new radiological score for PE.

BACKGROUND: The aim of the study was to investigate the association between the proximal level of the clot and the severity of pulmonary embolism (PE). METHODS: The cohort consisted of 99 consecutive patients with PE diagnosed by multi-detector computed tomography. A new score was constructed by calculating the mean value of the largest affected vessel [sub-segmental = 1, segmental = 2, lobar = 3, main pulmonary artery (MPA) = 4] in each lung. RESULTS: A significant association was found between the most proximal level of PE and pulmonary artery obstruction index (PAOI) (P < 0.0001), right ventricular (RV)/left ventricular (LV) ratio (P < 0.0001), and PaO(2) (P = 0.004). No significant association was found between systolic blood pressure and the level of PE. Troponin-T was elevated in none of the sub-segmental, 5% of segmental, 20% of lobar, and in 56% of PEs in the MPA (P = 0.001). Significant association was found between the proposed score and PAOI (P < 0.0001), RV/LV ratio (P < 0.0001), PaO(2) (P < 0.008). Troponin-T was elevated in 10% of level 1, 0% of level 2, 43% level of 3, 66% of level 4 PE (P < 0.0001). Cut-off level score 4 yielded a sensitivity of 84% and a specificity of 74% for the detection of elevated troponin-T. CONCLUSIONS: In conclusion, the study indicates that both the most proximal level of PE and the proposed score are related to the severity of PE as determined by blood oxygenation, biochemical and radiological parameters and could therefore be of value for rapid risk stratification of PE. However, the prognostic value of these classifications and their clinical significance needs to be evaluated in properly designed studies.

D-dimer level is associated with the extent of pulmonary embolism.

OBJECTIVES: Our aim was to study the association between the level of D-dimer and the severity of pulmonary embolism (PE) as determined by various biochemical and radiological prognostic markers in order to investigate the potential value of D-dimer as a prognostic marker for the severity of PE. PATIENTS AND METHODS: PE was diagnosed in 100 consecutive out-patients by multi-detector computerized tomography. One patient was excluded and the final cohort consisted of 99 patients. Pulmonary Artery Obstruction Index (PAOI) and Right Ventricular/Left Ventricular (RV/LV) ratio were assessed. RESULTS: The median value for D-dimer was 5.0 mg/L (inter-quartile range: 1.8, 12.2). There was a significant association between log D-dimer, and between log RV/LV (r=0.45), log PAOI (r=0.5), and PaO(2) (r=0.40). The multivariate analysis showed an increased association between log D-dimer and between log RV/LV ratio (r=0.54) and log PAOI (r=0.52) after adjusting for age, gender and for the duration of symptoms. Significant association was found between the level of D-dimer and the most proximal level of PE (p<0.0005). There was a significant dose-response relationship between the level D-dimer and between Troponin-T and the frequency of thrombolysis (p<0.0005). In the subgroup of patients with D-Dimer over the upper quartile (>12.2), 12 (67%) patients had elevated Troponin-T and 8 (32%) patients received thrombolysis, compared to 1 (5%) patient with elevated Troponin-T and none treated with thrombolysis in the subgroup of patients with D-dimer

Validation of a new D-dimer microparticle enzyme immunoassay (AxSYM D-Dimer) in patients with suspected pulmonary embolism (PE).

OBJECTIVES: The aim of the study was to evaluate a new automated assay for D-dimer testing (AxSYM D-Dimer) based on microparticle enzyme-immunoassay technology by comparing it with three well established D-dimer assays. PATIENTS AND METHODS: The performance of the new assay was evaluated in 280 plasma samples that were collected prospectively from out-patients included in a management study evaluating a decision based algorithm. RESULTS: 58/280 patients (21%) had PE diagnosed by CT. Median values of AxSYM D-dimer in patients with PE were 3689 ng/mL (range 775-9000). Comparison analysis displayed excellent agreement with VIDAS (kappa=0.84) and Asserachrom (kappa=0.81) D-dimer assays. A strong correlation was found between AxSYM and the VIDAS (r=0.96) and Asserachrom (r=0.89) D-dimer assays. The highest cut-off value for AxSYM that yielded a sensitivity of 100% was 765 ng/mL with a specificity of 50%. At the cut-off level <500 ng/mL, the sensitivity and specificity of AxSYM D-dimer were 100% and 34%; VIDAS 100% and 42%; Asserachrom 100% and 40%; and STALiatest 100% and 37%, respectively. AxSYM D-dimer was negative in 75 patients (33.8%). None of these had PE at the initial work-up or VTE during the 3-month follow-up. CONCLUSIONS: AxSYM D-dimer seems to be safe and effective in ruling out PE in out-patients. The cut-off level can be set at 500 to 750 ng/mL, at which the assay displays a performance that is comparable to that of the ELISA based assays. However, further studies are needed to confirm the safety of the assay and to determine the most optimal cut-off level in patients with venous thromboembolism.

The performance of STA-Liatest D-dimer assay in out-patients with suspected pulmonary embolism.

Several studies have shown that D-dimer can reliably rule out pulmonary embolism (PE) in out-patients. However, various assays have different sensitivities and specificities to detect thrombosis. Our aim was to evaluate the performance of STA-Liatest D-Di in out-patients referred for suspected PE in a prospective outcome study. 495 consecutive patients referred to Østfold Hospital Trust-Fredrikstad, Norway for suspected PE between February 2002 and December 2003, were recruited in a study evaluating a decision-based algorithm combining clinical probability (CP), D-dimer, and multi-slice computer tomography (MSCT). D-dimer was performed as a first step test. No further testing was carried out in patients with D-dimer < or =0.4 mg/l and low/intermediate CP. The remaining patients proceeded to MSCT. All patients were followed up for 3 months to assess the 3-month thromboembolic risk. The final cohort consisted of 432 patients. PE was diagnosed in 102 (23%) patients. At a D-dimer cut-off point of 0.4 mg/l the tests had the highest sensitivity (100%) and specificity (36%). It safely ruled out PE in 120 (28%) patients. Kappa-coefficients for comparisons versus VIDAS and Asserachrom showed good concordance. STA-Liatest is a reliable and effective assay that can safely rule out PE in out-patients with a performance comparable with that of enzyme-linked immunosorbent assay-based d-dimer levels.

Management of suspected pulmonary embolism (PE) by D-dimer and multi-slice computed tomography in outpatients: an outcome study.

OBJECTIVES: A prospective outcome study designed to evaluate a simple strategy for the management of outpatients with suspected pulmonary embolism (PE), based on clinical probability, D-dimer, and multi-slice computed tomography (MSCT). METHODS: A cohort of 432 consecutive patients admitted to the emergency department with suspected PE was managed by sequential non-invasive testing. Patients in whom PE was ruled out were not given anticoagulants, but were followed-up for 3 months. RESULTS: Normal D-dimer and low-intermediate clinical probability ruled out PE in 103 patients [24% (95% CI 20-28)]. Seventeen patients had normal D-dimer, but high clinical probability and proceeded to MSCT. All patients proved negative for PE. A total of 329 (76%) patients underwent MSCT examination. Pulmonary embolism was diagnosed in 93 patients [21.5% (95% CI 18-26)] and was ruled out by negative MSCT in 221 patients [51% (95% CI 46-56)]. MSCT scans were determined as inconclusive in 15 (4.5%) patients. No patient developed objectively verified venous thromboembolism (VTE) during the 3-month follow-up period. However, the cause of death was adjudicated as possibly related to PE in two patients, resulting in an overall 3-month VTE risk of 0.6% (95% CI 0-2.2%). The diagnostic algorithm yielded a definite diagnosis in 96.5% of the patients. CONCLUSIONS: This simple and non-invasive strategy combining clinical probability, D-dimer, and MSCT for the management of outpatients with suspected PE appears to be safe and effective.

[Time delay in the thrombolytic treatment of myocardial infarction]. / Tidsforsinkelse ved trombolytisk behandling av hjerteinfarkt.

INTRODUCTION: Thrombolytic treatment is central in the treatment of patients with myocardial infarction. MATERIAL AND METHODS: A cross-sectional study was conducted to determine the time delay incurred in thrombolytic treatment of patients with myocardial infarction in Ostfold Hospital, Fredrikstad, Norway. Over a seven-month period, 317 patients were diagnosed as having myocardial infarction. 80 patients (25%) received thrombolytic therapy, 68 of whom (85%) were eligible for the study. 12 patients were excluded either because of not meeting the inclusion criteria or because of incomplete data. RESULTS: The following median times were recorded: from onset of chest pain till first contact with the health care services, 59 minutes; from first contact till arrival at hospital, 32 minutes; from hospital arrival till initiation of treatment, 40 minutes; from onset of chest pain till initiation of treatment, 147 minutes. 38% of the patients received thrombolysis within 120 minutes of pain onset, and 35% received treatment within 30 minutes of arrival in hospital. There was no difference in time delay before contacting health care services among patients with or without a previous history of coronary heart disease, except for those who took nitroglycerine at onset of symptoms. They had the longest time delay. INTERPRETATION: In order to reduce time delay, doctors should give better instructions to patients with a previous history of coronary heart disease and conduct regular training programmes for hospital interns and nurses. It is further assumed that prehospital ECG and direct admission to the coronary care unit, or initiation of thrombolysis in the emergency department or in the ambulance, would result in a considerable reduction in time delay.