Jeannine Kassis

A COMPARISON OF THREE MONTHS OF ANTICOAGULATION WITH EXTENDED ANTICOAGULATION FOR A FIRST EPISODE OF IDIOPATHIC VENOUS THROMBOEMBOLISM

BACKGROUND Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. METHODS In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. RESULTS A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). CONCLUSIONS Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.

Determinants and Time Course of the Postthrombotic Syndrome after Acute Deep Venous Thrombosis

BACKGROUND The reason some patients with deep venous thrombosis (DVT) develop the postthrombotic syndrome is not well understood. OBJECTIVE To determine the frequency, time course, and predictors of the postthrombotic syndrome after acute DVT. DESIGN Prospective, multicenter cohort study. SETTING 8 Canadian hospital centers. PATIENTS 387 outpatients and inpatients who received an objective diagnosis of acute symptomatic DVT were recruited from 2001 to 2004. MEASUREMENTS Standardized assessments for the postthrombotic syndrome using the Villalta scale at 1, 4, 8, 12, and 24 months after enrollment. Mean postthrombotic score and severity category at each interval was calculated. Predictors of postthrombotic score profiles over time since diagnosis of DVT were identified by using linear mixed modeling. RESULTS At all study intervals, about 30% of patients had mild (score, 5 to 9), 10% had moderate (score, 10 to 14), and 3% had severe (score >14 or ulcer) postthrombotic syndrome. Greater postthrombotic severity category at the 1-month visit strongly predicted higher mean postthrombotic scores throughout 24 months of follow-up (1.97, 5.03, and 7.00 increase in Villalta score for mild, moderate, and severe 1-month severity categories, respectively, vs. none; P < 0.001). Additional predictors of higher scores over time were venous thrombosis of the common femoral or iliac vein (2.23 increase in score vs. distal [calf] venous thrombosis; P < 0.001), higher body mass index (0.14 increase in score per kg/m(2); P < 0.001), previous ipsilateral venous thrombosis (1.78 increase in score; P = 0.001), older age (0.30 increase in score per 10-year age increase; P = 0.011), and female sex (0.79 increase in score; P = 0.020). LIMITATIONS Decisions to prescribe compression stockings were left to treating physicians rather than by protocol. Because international normalized ratio data were unavailable, the relationship between anticoagulation quality and Villalta scores could not be assessed. CONCLUSION The postthrombotic syndrome occurs frequently after DVT. Patients with extensive DVT and those with more severe postthrombotic manifestations 1 month after DVT have poorer long-term outcomes.

Determinants of health-related quality of life during the 2 years following deep vein thrombosis.

Summary.  Background/objectives: We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post‐thrombotic syndrome (PTS). Patients/methods: Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self‐completed. Generic QOL was measured using the Short‐Form Health Survey‐36 (SF‐36) questionnaire. Venous disease‐specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)‐QOL/Sym questionnaire. The change in QOL scores over a 2‐year follow‐up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. Results: Among the 387 patients recruited, the average age was 56 years, two‐thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow‐up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P‐values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES‐QOL and VEINES‐Sym). Multivariable regression analyses showed that PTS (P < 0.0001), age (P = 0.0009), proximal DVT (P = 0.01) and inpatient status (P = 0.04) independently predicted 2‐year SF‐36 PCS scores. PTS alone independently predicted 2‐year VEINES‐QOL (P < 0.0001) and VEINES‐Sym (P < 0.0001) scores. Conclusions: Development of PTS is the principal determinant of health‐related QOL 2 years after DVT. Our study provides prognostic information on patient‐reported outcomes after DVT and emphasizes the need for effective prevention and treatment of the PTS.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Predictors of the post‐thrombotic syndrome during long‐term treatment of proximal deep vein thrombosis

Summary.  Background: The post‐thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). Objectives: To evaluate predictors of the post‐thrombotic syndrome, including intensity of long‐term anticoagulation, and to assess the impact of the post‐thrombotic syndrome on quality of life. Patients and methods: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty‐five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional‐intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long‐term warfarin therapy (target INR 2.5 vs. INR 1.7). Post‐thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease‐specific quality of life was compared in patients with and without the post‐thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post‐thrombotic syndrome and of its severity. Results: After an average follow‐up of 2.2 years, the prevalence of post‐thrombotic syndrome was 37% and of severe post‐thrombotic syndrome was 4%. Quality of life was worse in patients with the post‐thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post‐thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post‐thrombotic syndrome. Conclusions: The post‐thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long‐term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post‐thrombotic syndrome, this finding requires further evaluation in prospective studies.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor

Summary.  Background: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. Methods: In this double‐blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow‐up. Results:  Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) − 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient‐year in those who received warfarin for 1 month and 3.2% per patient‐year in those who received warfarin for 3 months (rate difference of 3.6% per patient‐year; 95% CI − 3.8, 11.0). There were no major bleeds in either group. Conclusion: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia

PURPOSE X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy. PATIENTS AND METHODS Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m(2)) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m(2) in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA. RESULTS Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m(2) of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m(2) AEG35156. Among the patients receiving 350 mg/m(2) of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156. CONCLUSION At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.

Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation

Summary.  Background: Few studies have evaluated the long‐term economic consequences of deep vein thrombosis (DVT). None of them have incorporated prospectively collected clinical data to ensure accurate identification of incident cases of DVT and DVT‐related health outcomes of interest, such as post‐thrombotic syndrome (PTS). Objectives: To prospectively quantify medical and non‐medical resource use and costs related to DVT during 2 years following diagnosis, and to identify clinical determinants of costs. Methods: Three hundred and fifty‐five consecutive patients with acute DVT were recruited at seven Canadian hospital centers. Resource use and cost information were retrieved from three sources: weekly patient‐completed cost diaries, nurse‐completed case report forms, and the Quebec provincial administrative healthcare database (RAMQ). Results: The rate of DVT‐related hospitalization was 3.5 per 100 patient‐years (95% confidence interval [CI] 2.2–4.9). Patients reported a mean (standard deviation) of 15.0 (14.5) physician visits and 0.7 (1.2) other healthcare professional visits. The average cost of DVT was

Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial

5180 (95% CI

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia

4344–6017) in Canadian dollars, with 51.6% of costs being attributable to non‐medical resource use. Multivariate analysis identified four independent predictors of costs: concomitant pulmonary embolism (relative increase in cost [RIC] 3.16; 95% CI 2.18–4.58), unprovoked DVT (RIC 1.65; 95% CI 1.28–2.13), development of PTS during follow‐up (RIC 1.35; 95% CI 1.05–1.74), and management of DVT in the inpatient setting (RIC 1.79; 95% CI 1.33–2.40). Conclusions: The economic burden of DVT is substantial. The use of measures to prevent the occurrence of PTS and favoring outpatient care of DVT has the potential to diminish costs.