Jacqueline M. Cohen

Pharmacologic and Compression Therapies for Postthrombotic Syndrome: A Systematic Review of Randomized Controlled Trials

BACKGROUND Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS. METHODS We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature. RESULTS A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score. CONCLUSIONS There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

Original ResearchAntithrombotic TherapyPharmacologic and Compression Therapies for Postthrombotic Syndrome: A Systematic Review of Randomized Controlled Trials

BACKGROUND Postthrombotic syndrome (PTS) is a frequent, chronic complication of DVT. The effectiveness and safety of available treatments are unknown. The objective of this study was to systematically review the literature to assess whether pharmacologic and compression therapies are effective and safe for the treatment of PTS. METHODS We sought to identify randomized controlled trials (RCTs) via a search of PubMed, studies referenced in included publications, and studies that cited relevant literature. RESULTS A total of 121 titles were reviewed, 12 full-text publications were assessed for inclusion, and seven RCTs, including 703 patients, were selected for inclusion. Four trials assessed the effectiveness of drugs, including rutosides, hidrosmin, and defibrotide, and four trials assessed compression therapies for treatment of PTS. Systems for the diagnosis and classification of PTS severity varied across studies. Three of four drug therapy trials reported moderate improvement in selected PTS symptoms, minor changes in calf and ankle circumference, and some effects on ulcer healing. Two studies of compression stockings did not report benefit. Two studies that assessed compression devices reported improvement in PTS symptoms scores; one of these reported an improvement in quality-of-life score. CONCLUSIONS There is limited and low-quality evidence for the effectiveness of rutosides, hidrosmin, defibrotide, and compression stockings, but moderate-quality evidence that supports the use of intermittent compression to provide at least short-term relief from PTS. More rigorous studies are needed to assess the short- and long-term effectiveness and safety of PTS therapies.

Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis.

The postthrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT), occurring in 20–40% of patients. Identifying risk factors for PTS may be useful to provide patients with prognostic information and target prevention strategies.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome

Post‐thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT).

Predictive value of markers of inflammation in the postthrombotic syndrome: a systematic review Inflammatory biomarkers and PTS

BACKGROUND The postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT). Inflammation may contribute to its pathophysiology. OBJECTIVES We conducted a systematic review of studies that analyzed the association between biomarkers of inflammation and PTS in DVT patients. METHODS The electronic databases PubMed, EMBASE, Medline, Scopus and Web of Science were searched for studies published until March 2015 that measured blood inflammation biomarker levels in adult DVT patients and reported their association with PTS development. Two reviewers independently performed full text assessment and data extraction. RESULTS Ten studies were included. Nine reported on the association between C-reactive protein and PTS; Interleukin (IL)-6 was measured in six studies; IL-8 in four studies; Intracellular adhesion molecule (ICAM)-1 in three studies; IL-10 and vascular cell adhesion molecule-1 in two studies; and monocyte chemotactic protein-1, matrix metalloprotease-9, P-Selectin, tumor necrosis factor α and erythrocyte sedimentation rate were measured in one study. Studies differed in terms of populations included, exclusion criteria, methods used for biomarker measurement and statistical measures of association between biomarkers and PTS. We were able to metaanalyze results only for IL-6 and found no significant association. Descriptively, ICAM-1 was significantly associated with PTS in two out of three studies that measured it. Other biomarkers did not demonstrate a significant association with PTS. CONCLUSIONS Our systematic review found conflicting results regarding the role of inflammatory biomarkers as predictors of PTS. ICAM -1 appears to be a promising marker for further investigation.

Maternal Antioxidant Levels in Pregnancy and Risk of Preeclampsia and Small for Gestational Age Birth: A Systematic Review and Meta-Analysis

Background Oxidative stress in preeclampsia and small for gestational age (SGA) birth suggests antioxidant supplementation could prevent these conditions. However, it remains unclear whether maternal antioxidant levels are systematically lower in these pregnancies. Objective To conduct a systematic review of the association between maternal antioxidant levels during pregnancy and preeclampsia or SGA. Methods We searched PubMed, Embase, and several other databases from 1970–2013 for observational studies that measured maternal blood levels of non-enzymatic antioxidants (vitamins A, C, E, and carotenoids) during pregnancy or within 72 hours of delivery. The entire review process was done in duplicate. Study quality was assessed using the Newcastle-Ottawa Scale and additional questions. We pooled the standardized mean difference (SMD) across studies, stratified by outcome and pregnancy trimester, and investigated heterogeneity using meta-regression. Results We reviewed 1,882 unique citations and 64 studies were included. Most studies were small with important risk of bias. Among studies that addressed preeclampsia (n = 58) and SGA (n = 9), 16% and 66%, respectively, measured levels prior to diagnosis. The SMDs for vitamins A, C, and E were significantly negative for overall preeclampsia, but not for mild or severe preeclampsia subtypes. Significant heterogeneity was observed in all meta-analyses and most could not be explained. Evidence for lower carotenoid antioxidants in preeclampsia and SGA was limited and inconclusive. Publication bias appears likely. Conclusions Small, low-quality studies limit conclusions that can be drawn from the available literature. Observational studies inconsistently show that vitamins C and E or other antioxidants are lower in women who develop preeclampsia or SGA. Reverse causality remains a possible explanation for associations observed. New clinical trials are not warranted in light of this evidence; however, additional rigorous observational studies measuring antioxidant levels before clinical detection of preeclampsia and SGA may clarify whether levels are altered at a causally-relevant time of pregnancy.

The predictive value of markers of fibrinolysis and endothelial dysfunction in the post thrombotic syndrome. A systematic review.

The post thrombotic syndrome (PTS) develops in 20-40% of deep venous thrombosis (DVT) patients. Risk factors for PTS have not been well elucidated. Identification of risk factors would facilitate individualised risk assessment for PTS. We conducted a systematic review to determine whether biomarkers of fibrinolysis or endothelial dysfunction can predict the risk for PTS among DVT patients. Studies were identified by searching the electronic databases PubMed, EMBASE, Scopus and Web of science. We included studies published between 1990 and 2013, measured biomarker levels in adult DVT patients, and reported rates of PTS development. Fourteen studies were included: 11 investigated the association between D-dimer and PTS; three examined fibrinogen; two measured von Willebrand factor; one measured plasminogen activator inhibitor-1; one assessed ADAMTS-13 (A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats) and one measured factor XIII activity. Studies varied with regards to inclusion criteria, definition of PTS, time point and method of biomarker measurement. We were unable to meta-analyse results due to marked clinical heterogeneity. Descriptively, a significant association with PTS was found for D-dimer in four studies and factor XIII in one study. Further prospective research is needed to elucidate whether these markers might be useful to predict PTS development.

The association between maternal antioxidant levels in midpregnancy and preeclampsia

OBJECTIVE We sought to determine whether midpregnancy antioxidant levels are associated with preeclampsia, overall and by timing of onset. STUDY DESIGN We carried out a case-control study, nested within a cohort of 5337 pregnant women in Montreal, Quebec, Canada. Blood samples obtained at 24-26 weeks were assayed for nonenzymatic antioxidant levels among cases of preeclampsia (n = 111) and unaffected controls (n = 441). We excluded women diagnosed with gestational hypertension only. We used logistic regression with the z-score of each antioxidant level as the main predictor variable for preeclampsia risk. We further stratified early-onset (<34 weeks) and late-onset preeclampsia and carried out multinomial logistic regression. Finally, we assessed associations between antioxidant biomarkers and timing of onset (in weeks) by Cox regression, with appropriate selection weights. We summed levels of correlated biomarkers (r(2) > 0.3) and log-transformed positively skewed distributions. We adjusted for body mass index, nulliparity, preexisting diabetes, hypertension, smoking, and proxies for ethnicity and socioeconomic status. RESULTS The odds ratios for α-tocopherol, α-tocopherol:cholesterol, lycopene, lutein, and carotenoids (sum of α-carotene, β-carotene, anhydrolutein, α-cryptoxanthin, and β-cryptoxanthin) suggested an inverse association between antioxidant levels and overall preeclampsia risk; however, only lutein was significantly associated with overall preeclampsia in adjusted models (odds ratio, 0.60; 95% confidence interval, 0.46-0.77) per SD. In multinomial logistic models, the relative risk ratio (RRR) estimates for the early-onset subgroup were farther from the null than those for the late-onset subgroup. The ratio of α-tocopherol to cholesterol and retinol were significantly associated with early- but not late-onset preeclampsia: RRRs (95% confidence intervals) for early-onset preeclampsia 0.67 (0.46-0.99) and 1.61 (1.12-2.33), respectively. Lutein was significantly associated with both early- and late-onset subtypes in adjusted models; RRRs 0.53 (0.35-0.80) and 0.62 (0.47-0.82), respectively. Survival analyses confirmed these trends. CONCLUSION Most antioxidants were more strongly associated with early-onset preeclampsia, suggesting that oxidative stress may play a greater role in the pathophysiology of early-onset preeclampsia. Alternatively, reverse causality may explain this pattern. Lutein was associated with both early- and late-onset preeclampsia and may be a promising nutrient to consider in preeclampsia prevention trials, if this finding is corroborated.

Surgical Treatment of Moderate-to-Severe Post-Thrombotic Syndrome

BACKGROUND Severe post-thrombotic syndrome (PTS) occurs in 5% to 10% of patients after deep venous thrombosis. Medical therapy such as compression has limited effectiveness for the treatment of such patients. The objective of this study was to systematically review the effectiveness and safety of surgical approaches for the treatment of moderate-to-severe PTS. METHOD A computerized search was conducted using PubMed and reverse citation searches to retrieve English- and French-language articles, published after 1980, reporting on the endovascular and surgical treatment of PTS. RESULTS Three hundred three titles were retrieved, of which 28 full publications were reviewed. Twelve articles met criteria for inclusion, reporting on 349 patients. Surgical techniques included vein dilation and stent placement (two studies), venous bypass grafting (two studies), endophlebectomy with reconstruction (one study), valve reconstruction/transplant (six studies), and interruption of perforating veins (one study). Follow-up periods ranged from 1 month to 5 years. Eleven of 12 included studies described improvement in PTS after the given surgical intervention. Seven of 12 studies found improvement in all anatomic measures assessed (e.g., venous valve competency and patency, venous filling times, or ambulant venous pressure), and 11 of 12 studies reported clinical improvement (e.g., improvement in signs and symptoms, ulcer healing, ability to return to work, or reduced need for elastic compression stockings), with rates of ulcer healing ranging from 50% to 100%. Eight of 12 studies (representing 264 patients) reported safety outcomes. Complications reported most frequently were hematoma/seroma formation and wound infection, with no reported instances of mortality or pulmonary embolism. Limitations of the studies included a lack of randomized controlled trials, absence of control groups, small sample sizes, short follow-up periods, retrospective data collection, imprecise definition of PTS, heterogeneity of study participants, and, in three studies, lack of reporting on procedure safety. CONCLUSION Surgical and endovascular treatment of moderate-to-severe PTS could have the potential to be effective where conservative and medical treatments have failed. Our review describes studies of surgical techniques to treat PTS, but highlights important limitations of such studies. Further research using stricter research methodology is needed to evaluate the potential role of surgical techniques for the treatment of moderate-to-severe PTS.

Insufficient Milk Supply and Breast Cancer Risk: A Systematic Review

Background An association between insufficient milk supply, the inability of a mothers breast milk to provide sufficiently for her infant, and breast cancer has been suggested by observations in animal models. To determine if an association has been reported in epidemiological studies of human breast cancer, a systematic review of the literature has been conducted. We also sought to identify the methodological limitations of existing studies to guide the design of any future prospective studies in this field. Methodology/Principal Findings PubMed, EMBASE, Web of Science, BIOSIS, and CAB abstracts were searched. We selected any study that (1) assessed breast cancer in association with breastfeeding history and (2) examined the relationship between insufficient milk supply with breast cancer. Seven relevant studies were identified that met both criteria. There was statistically significant heterogeneity among the results which likely reflects clinically significant differences in definitions of insufficient milk supply and reference groups that were used. Among premenopausal women who had experienced insufficient milk supply, odds ratios (ORs) for breast cancer risk ranged from 0.9 to 16.3. Among postmenopausal women, ORs ranged from 0.6 to 6.7. Based on the range of odds ratios obtained in the studies reported in this review, it remains unclear if there is a true association between insufficient milk supply and breast cancer. Conclusions/Significance Although some studies have shown a strong positive association, there is no consistent evidence for an effect of insufficient milk supply on breast cancer risk. Exposure definitions are in need of improvement in order to focus on primary insufficient milk supply. Reference groups consisting of women who have successfully breastfed may also introduce positive bias (inflation of the odds ratio) into study results because of the protective effect of prolonged breastfeeding in the control group.