Mira Johri

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.

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

Effectiveness of compression stockings to prevent the post-thrombotic syndrome (The SOX Trial and Bio-SOX biomarker substudy): a randomized controlled trial

5180 (95% CI

Guidance on priority setting in health care (GPS-Health): the inclusion of equity criteria not captured by cost-effectiveness analysis

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.

CAN COST-EFFECTIVENESS ANALYSIS INTEGRATE CONCERNS FOR EQUITY? SYSTEMATIC REVIEW

BackgroundPost thrombotic syndrome (PTS) is a burdensome and costly complication of deep venous thrombosis (DVT) that develops in 20–40% of patients within 1–2 years after symptomatic DVT. Affected patients have chronic leg pain and swelling and may develop ulcers. Venous valve disruption from the thrombus itself or thrombus-associated mediators of inflammation is considered to be a key initiating event for the development of venous hypertension that often underlies PTS. As existing treatments for PTS are extremely limited, strategies that focus on preventing the development of PTS in patients with DVT are more likely to be effective and cost-effective in reducing its burden. Elastic compression stockings (ECS) could be helpful in preventing PTS; however, data on their effectiveness are scarce and conflicting.Methods/DesignThe SOX Trial is a randomized, allocation concealed, double-blind multicenter clinical trial. The objective of the study is to evaluate ECS to prevent PTS. A total of 800 patients with proximal DVT will be randomized to one of 2 treatment groups: ECS or placebo (inactive) stockings worn on the DVT-affected leg daily for 2 years. The primary outcome is the incidence of PTS during follow-up. Secondary outcomes are severity of PTS, venous thromboembolism (VTE) recurrence, death from VTE, quality of life and cost-effectiveness. Outcomes will be evaluated during 6 clinic visits and 2 telephone follow ups. At baseline, 1 and 6 months, blood samples will be obtained to evaluate the role of inflammatory mediators and genetic markers of thrombophilia in the development of PTS (Bio-SOX substudy).DiscussionThe SOX Trial will be the largest study and the first with a placebo control to evaluate the effectiveness of ECS to prevent PTS. It is designed to provide definitive data on the effects of ECS on the occurrence and severity of PTS, as well as DVT recurrence, cost-effectiveness and quality of life. This study will also prospectively evaluate the predictive role of biomarkers that are reflective of putative underlying pathophysiological mechanisms in the development of clinical PTS. As such, our results will impact directly on the care of patients with DVT.Trial RegistrationNCT00143598 and ISRCTN71334751

The cost-effectiveness of preventing mother-to-child transmission of HIV in low- and middle-income countries: systematic review.

This Guidance for Priority Setting in Health Care (GPS-Health), initiated by the World Health Organization, offers a comprehensive map of equity criteria that are relevant to health care priority setting and should be considered in addition to cost-effectiveness analysis. The guidance, in the form of a checklist, is especially targeted at decision makers who set priorities at national and sub-national levels, and those who interpret findings from cost-effectiveness analysis. It is also targeted at researchers conducting cost-effectiveness analysis to improve reporting of their results in the light of these other criteria.The guidance was develop through a series of expert consultation meetings and involved three steps: i) methods and normative concepts were identified through a systematic review; ii) the review findings were critically assessed in the expert consultation meetings which resulted in a draft checklist of normative criteria; iii) the checklist was validated though an extensive hearing process with input from a range of relevant stakeholders.The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others).

Birth Preparedness and Complication Readiness (BPCR) interventions to reduce maternal and neonatal mortality in developing countries: systematic review and meta-analysis

OBJECTIVES The aim of this study was to promote approaches to health technology assessment (HTA) that are both evidence-based and values-based. We conducted a systematic review of published studies describing formal methods to consider equity in the context of cost-effectiveness analysis (CEA). METHODS Candidate studies were identified through an unrestricted search of the Pub Med and EMBASE databases. The search closed on January 20, 2011. We identified additional studies by consulting experts and checking article bibliographies. Two authors independently reviewed each candidate study to determine inclusion and extracted data from studies retained for review. In addition to documenting methods, data extraction identified implicit and explicit notions of fairness. Data were synthesized in narrative form. Study quality was not assessed. RESULTS Of the 695 candidate articles, 51 were retained for review. We identified three broad methods to facilitate quantitative consideration of equity concerns in economic evaluation: integration of distributional concerns through equity weights and social welfare functions, exploration of the opportunity costs of alternative policy options through mathematical programming, and multi-criteria decision analysis. CONCLUSIONS Several viable techniques to integrate equity concerns within CEA now exist, ranging from descriptive approaches to the quantitative methods studied in this review. Two obstacles at the normative level have impeded their use in decision making to date: the multiplicity of concepts and values discussed under the rubric of equity, and the lack of a widely accepted normative source on which to ground controversial value choices. Clarification of equity concepts and attention to procedural fairness may strengthen use of these techniques in HTA decision making.

Strategies to increase the demand for childhood vaccination in low- and middle-income countries: a systematic review and meta-analysis

BackgroundAlthough highly effective prevention interventions exist, the epidemic of paediatric HIV continues to challenge control efforts in resource-limited settings. We reviewed the cost-effectiveness of interventions to prevent mother-to-child transmission (MTCT) of HIV in low- and middle-income countries (LMICs). This article presents syntheses of evidence on the costs, effects and cost-effectiveness of HIV MTCT strategies for LMICs from the published literature and evaluates their implications for policy and future research.MethodsCandidate studies were identified through a comprehensive database search including PubMed, Embase, Cochrane Library, and EconLit restricted by language (English or French), date (January 1st, 1994 to January 17th, 2011) and article type (original research). Articles reporting full economic evaluations of interventions to prevent or reduce HIV MTCT were eligible for inclusion. We searched article bibliographies to identify additional studies. Two authors independently assessed eligibility and extracted data from studies retained for review. Study quality was appraised using a modified BMJ checklist for economic evaluations. Data were synthesised in narrative form.ResultsWe identified 19 articles published in 9 journals from 1996 to 2010, 16 concerning sub-Saharan Africa. Collectively, the articles suggest that interventions to prevent paediatric infections are cost-effective in a variety of LMIC settings as measured against accepted international benchmarks. In concentrated epidemics where HIV prevalence in the general population is very low, MTCT strategies based on universal testing of pregnant women may not compare well against cost-effectiveness benchmarks, or may satisfy formal criteria for cost-effectiveness but offer a low relative value as compared to competing interventions to improve population health.Conclusions and RecommendationsInterventions to prevent HIV MTCT are compelling on economic grounds in many resource-limited settings and should remain at the forefront of global HIV prevention efforts. Future cost-effectiveness analyses can help to ensure that pMTCT interventions for LMICs reach their full potential by focussing on unanswered questions in four areas: local assessment of rapidly evolving HIV MTCT options; strategies to improve coverage and reach underserved populations; evaluation of a more comprehensive set of MTCT approaches including primary HIV prevention and reproductive counselling; integration of HIV MTCT and other sexual and reproductive health services.