Waleed Ghanima

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

Summary.  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.

How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment

The paradigm for managing primary immune thrombocytopenia (ITP) in adults has changed with the advent of rituximab and thrombopoietin receptor agonists (TPO-RAs) as options for second-line therapy. Splenectomy continues to provide the highest cure rate (60%-70% at 5+ years). Nonetheless, splenectomy is invasive, irreversible, associated with postoperative complications, and its outcome is currently unpredictable, leading some physicians and patients toward postponement and use of alternative approaches. An important predicament is the lack of studies comparing second-line options to splenectomy and to each other. Furthermore, some adults will improve spontaneously within 1-2 years. Rituximab has been given to more than 1 million patients worldwide, is generally well tolerated, and its short-term toxicity is acceptable. In adults with ITP, 40% of patients are complete responders at one year and 20% remain responders at 3-5 years. Newer approaches to using rituximab are under study. TPO-RAs induce platelet counts > 50 000/μL in 60%-90% of adults with ITP, are well-tolerated, and show relatively little short-term toxicity. The fraction of TPO-RA-treated patients who will be treatment-free after 12-24 months of therapy is unknown but likely to be low. As each approach has advantages and disadvantages, treatment needs to be individualized, and patient participation in decision-making is paramount.

Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial

BACKGROUND Post-thrombotic syndrome is a common complication after acute proximal deep vein thrombosis (DVT) and is associated with reduced quality of life and a substantial cost burden. In the 2-year results of the CaVenT study, additional catheter-directed thrombolysis reduced the risk of post-thrombotic syndrome by 14% compared with conventional therapy, but did not affect quality of life. In this study we report results at the 5-year follow-up, aiming to assess whether findings for post-thrombotic syndrome and quality of life have persisted. METHODS Between Jan 3, 2006, and Dec 22, 2009, we recruited patients aged 18-75 years with a first-time high proximal leg DVT from 20 hospitals in the Norwegian southeastern health region. With sealed envelopes, participants were randomly assigned (1:1) to standard treatment with compression stockings and anticoagulants (control group) or to standard treatment plus catheter-directed thrombolysis with alteplase within 21 days from symptom onset. Pre-specified outcomes in this analysis were post-thrombotic syndrome at 5 years as assessed with the Villalta score and scores for quality of life at 5 years with EQ-5D and the disease-specific VEINES-QOL/Sym. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00251771. FINDINGS At 5 year follow-up (last date Oct 14, 2014), data were available for 176 patients (84% of the 209 patients originally randomised)--87 originally assigned to catheter-directed thrombolysis and 89 originally assigned to the control group. 37 patients (43%; 95% CI 33-53) allocated to catheter-directed thrombolysis developed post-thrombotic syndrome, compared with 63 (71%; 95% CI 61-79) allocated to the control group (p<0·0001), corresponding to an absolute risk reduction of 28% (95% CI 14-42) and a number needed to treat of 4 (95% CI 2-7). Four (5%) patients assigned to catheter-directed thrombolysis and one (1%) to standard treatment had severe post-thrombotic syndrome (Villalta score ≥ 15 or presence of an ulcer). Quality-of-life scores with either assessment scale did not differ between the treatment groups. INTERPRETATION Additional catheter-directed thrombolysis resulted in a persistent and increased clinical benefit during follow-up for up to 5 years, supporting the use of additional catheter-directed thrombolysis in patients with extensive proximal DVT. However, allocation to this therapy did not lead to better quality of life. The optimal endovascular thrombolytic approach needs further investigation. FUNDING Southeastern Norway Regional Health Authority, the Research Council of Norway, University of Oslo, Oslo University Hospital.

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

Summary.  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.

Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND Immune thrombocytopenia is characterised by immune-mediated destruction and suboptimum production of platelets. Despite the absence of supporting evidence, rituximab is frequently used off-label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy-sparing treatment in patients who were previously treated with corticosteroids. METHODS In this multicentre, randomised, double-masked, placebo-controlled trial, we enrolled corticosteroid unresponsive adult patients (aged ≥18 years) with primary immune thrombocytopenia and a platelet count of less than 30 × 10(9) platelets per L. Patients were randomly assigned (1:1) to four weekly infusions of 375 mg/m(2) rituximab or placebo. Concurrent treatment with corticosteroids only was allowed during the study. The primary endpoint was rate of treatment failure within 78 weeks--a composite of splenectomy or meeting criteria for splenectomy after week 12 if splenectomy was not done, assessed in all patients who received at least one dose of study treatment. Secondary endpoints were response rates, relapse rates, and duration of response. Efficacy endpoints were assessed with the Kaplan-Meier method. Safety endpoints were assessed in all patients who received at least one dose. This trial is registered with ClinicalTrials.gov, number NCT00344149. FINDINGS Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients. 32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan-Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio [HR] 0·89, 95% CI 0·55-1·45; p=0·65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p=0·15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p=0·12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p=0·01) but not complete response (76 vs 49 weeks; p=0·19). Rates of bleeding were similar in the two groups (21 [38%] in the rituximab group vs 27 [50%] in the placebo group; p=0·08) as were rates of infection (22 [40%] vs 13 [24%]; p=0·09). INTERPRETATION Despite no reduction in the rate of long-term treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab. FUNDING South-East Regional Health Authority and Østfold Hospital, Norway; Roche, France; and Roche, Norway.

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).

Bone marrow fibrosis in 66 patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists: a single-center, long-term follow-up

Thrombopoietin-receptor agonists increase platelet counts by stimulating the thrombopoietin receptor. Bone marrow fibrosis has been reported in patients receiving thrombopoietin-receptor agonists. This study determined the extent of myelofibrosis, its clinical relevance, and incidence of phenotypic or karyotypic abnormalities in patients with immune thrombocytopenia treated with thrombopoietin-receptor agonists. The grade of myelofibrosis was assessed before (n=15), during (n=117) and after (n=9) treatment in bone marrow biopsies from 66 patients. The proportion of bone marrow biopsies showing no fibrosis (myelofibrosis grade 0) decreased from 67% pre-treatment to 22% at last biopsy, of which 59% had grade 1 myelofibrosis and 18% had grade 2 myelofibrosis. The median duration of treatment with thrombopoietin-receptor agonists to last bone marrow biopsies was 29 months; patients who had two or more biopsies significantly more frequently had myelofibrosis grades 2/3 in the last bone marrow biopsies as compared to the first. Older age was associated with higher grades of fibrosis. No differences in blood counts or lactate dehydrogenase levels were found between patients with myelofibrosis grades 0/1 and those with grade 2. No clonal karyotypic or immunophenotypic abnormalities emerged. This study found that thrombopoietin-receptor agonists induce myelofibrosis grades 2/3 in approximately one-fifth of patients with immume thrombocytopenia, increasingly with >2 years of treatment with thrombopoietin-receptor agonists. Annual/biannual follow-up with bone marrow biopsies is, therefore, recommended in patients being treated with thrombopoietin-receptor agonists in order to enable prompt discontinuation of these drugs should grades 2/3 myelofibrosis develop. Discontinuation of thrombopoietin-receptor agonists may prevent development of clinical manifestations by stopping progression of fibrosis in grade 2/3.

Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration.

Adults with newly diagnosed or persistent immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed immunothrombocytopenia, two studies showed that dexamethasone 40 mg/day × four days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown three cycles of dexamethasone are better than one and patients with persistent/chronic immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore, 375 mg/m2 × 4 rituximab was combined with three 4-day cycles of 28 mg/m2 (max. 40 mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count ≥100×109/L) or partial (50–99×109/L). Only 5 patients had not been previously treated. Fifty achieved complete (n=43, 64%) or partial (n=7, 10%) responses. Thirty-five of 50 responders maintained treatment-free platelet counts over 50×109/L at a median 17 months (range 4–67) projecting 44% event-free survival. Duration of immunothrombocytopenia less than 24 months, achieving complete responses, and being female were associated with better long-term response (P<0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9 of 12 evaluable patients recovered their IgG levels. Rituximab combined with three cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with one cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women and in patients within two years of diagnosis. (clinicaltrials.gov identifier:02050581)

A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants.

Aims We aimed to evaluate bleeding risk in clinical practice in patients with atrial fibrillation (AF) being prescribed dabigatran, rivaroxaban, or apixaban compared with warfarin. Methods Using nationwide registries (Norwegian Patient Registry and Norwegian Prescription Database), we identified AF patients with a first prescription of oral anticoagulants between January 2013 and June 2015. Patients were followed until discontinuation or switching of oral anticoagulants, death, or end of follow-up. The primary endpoint was major or clinically relevant non-major (CRNM) bleeding. Results In total 32 675 AF patients were identified (58% men, median age 74 years): 11 427 patients used warfarin, 7925 dabigatran, 6817 rivaroxaban, and 6506 apixaban. After a median follow-up of 173 days (25th, 75th percentile 84, 340), 2081 (6.37%) patients experienced a first major or CRNM bleeding. Using a Cox proportional hazard model adjusting for baseline characteristics, use of apixaban [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.61–0.80, P < 0.001] and dabigatran (HR 0.74, 95% CI 0.66–0.84, P < 0.001) were associated with a lower risk of major or CRNM bleeding compared with warfarin whereas use of rivaroxaban was not (HR: 1.05, 95% CI 0.94–1.17, P = 0.400). Use of dabigatran and rivaroxaban were associated with higher risk of gastrointestinal bleeding, whereas use of apixaban and dabigatran were associated with lower risk of intracranial bleeding, compared with warfarin. Conclusion In this nationwide cohort study in AF patients, apixaban and dabigatran were associated with a lower risk of major or CRNM bleeding compared with warfarin. The risk of gastrointestinal bleeding was higher with rivaroxaban and dabigatran compared with warfarin.

Thrombopoietin receptor agonist therapy in primary immune thrombocytopenia is associated with bone marrow hypercellularity and mild reticulin fibrosis but not other stromal abnormalities

Primary immune thrombocytopenia is an acquired autoimmune disorder characterized by platelet count of <100 × 109/l in the absence of other causes of thrombocytopenia. Primary immune thrombocytopenia is defined as ‘chronic’ when it has been present for more than 12 months without spontaneous remission or maintenance of complete response to therapy. Recently, thrombopoietin receptor agonists became available for treatment of chronic primary immune thrombocytopenia. Anecdotal reports have raised concerns about a possible association between therapy with thrombopoietin receptor agonists and an increase in bone marrow fibrosis. To investigate this association we studied eight patients with primary immune thrombocytopenia in detail comparing fibrosis and other morphological features in pre-therapy and on-therapy bone marrow biopsies, with the longest follow-up reported to date. A slight but significant increase to MF-1 in reticulin fibrosis was observed during therapy, but collagen was never present. On-therapy bone marrows were hypercellular due to panmyelosis with increased trilineage hematopoiesis. Megakaryocytes were increased in number, with acquisition of evident pleomorphism, nuclear hyperlobulation and tendency in some cases to form clusters. The overall picture of the on-therapy marrows was characterized by myeloproliferative neoplasm-like features, resembling essential thrombocythemia or occasionally early primary myelofibrosis. As thrombopoietin receptor agonists are becoming a mainstream treatment for primary immune thrombocytopenia, general pathologists and especially hematopathologists need to be aware of the characteristic morphological changes associated with use of these therapeutic agents, in order to avoid misdiagnosis of a myeloid neoplasm.