Impact of adjustment for quality on results of meta-analyses of diagnostic accuracy

BACKGROUND: We examined whether and to what extent different strategies of defining and incorporating quality of included studies affect the results of metaanalyses of diagnostic accuracy. METHODS: We evaluated the methodological quality of 487 diagnostic-accuracy studies in 30 systematic reviews with the QUADAS (Quality Assessment of Diagnostic-Accuracy Studies) checklist. We applied 3 strategies that varied both in the definition of quality and in the statistical approach to incorporate the quality-assessment results into metaanalyses. We compared magnitudes of diagnostic odds ratios, widths of their confidence intervals, and changes in a hypothetical clinical decision between strategies. RESULTS: Following 2 definitions of quality, we concluded that only 70 or 72 of 487 studies were of "high quality". This small number was partly due to poor reporting of quality items. None of the strategies for accounting for differences in quality led systematically to accuracy estimates that were less optimistic than ignoring quality in metaanalyses. Limiting the review to high-quality studies considerably reduced the number of studies in all reviews, with wider confidence intervals as a result. In 18 reviews, the quality adjustment would have resulted in a different decision about the usefulness of the test. CONCLUSIONS: Although reporting the results of quality assessment of individual studies is necessary in systematic reviews, reader wariness is warranted regarding claims that differences in methodological quality have been accounted for. Obstacles for adjusting for quality in metaanalyses are poor reporting of design features and patient characteristics and the relatively low number of studies in most diagnostic review

Von Willebrand factor, ADAMTS13 levels and prediction of venous thromboembolism in patients with cancer

Background: Cancer patients are at high risk for venous thromboembolism (VTE). However, thromboprophylaxis in these patients is associated with an increased hemorrhagic risk. The Khorana score is a risk scoring model for prediction of VTE that includes clinical and laboratory parameters. It has been expanded by incorporating two biomarkers, soluble P-selectin (P-sel), and D-Dimer. Other laboratory markers like prothrombin fragment 1 + 2 (F1 + 2) have also been reported to predict VTE in cancer patients. von Willebrand factor (VWF) is a mutimeric protein that promotes platelet adhesion and aggregation in high shear stress conditions; it is also implicated in venous thrombosis. ADAMTS13 (a desintegrin-like and métalloprot éase thrombospondin type 1 motif) specifically cleaves VWF multimers and subsequently regulates its activity; previous studies displayed decreased levels of ADAMTS13 in cancer patients when compared to patients without cancer. Aims: (i) to search for an association between VWF and ADAMTS13 levels and VTE in cancer patients; (ii) to compare Khorana score and expanded Khorana score before and after addition of VWF and ADAMTS13 levels. Methods: multicenter case-control study. Subjects were ambulatory patients receiving chemotherapy for stage III or IV cancer, prospectively followed for 6 months for the development of VTE. Each case (patient who developed VTE) was matched with seven controls (patients who did not develop VTE) for age, sex, type of cancer and stage. The Khorana score and the expanded score were calculated. ADAMTS13 activity was measured using a fluorescence resonance energy transfer assay; VWF, ADAMTS13 antigen, P-sel, D-Dimer and F1 + 2 levels were measured using ELISA methods. Univariate and multivariate analysis were performed to compare the levels between cases and controls. Logistic models were used to test whether VWF and ADAMTS13 levels would add significant prognostic information to Khorana and expanded Khorana score. Results are expressed as odds ratios (OR) and their 95% CIs. Results: We studied 20 cases and 140 controls. VWF levels were significantly higher in cases when compared to controls (326 ± 185% vs. 242 ± 158%; P = 0.02), whereas ADAMTS13 levels were not significantly different (activity 87 ± 18.9% vs. 81.5 ± 18.9; antigen 579 ± 108 ng/mL vs. 564 ± 137 ng/mL). VWF and ADAMTS13 levels were not correlated (r = -0.06 Pearson). VWF levels significantly increased with increasing stage of cancer (P = 0.03) whereas ADAMTS13 activity levels only tended to decrease (P = 0.06). The addition of VWF levels significantly improved the Khorana score (OR = 3.5 [1.2-10.2]). ADAMTS13 activity levels significantly improved the Khorana and the expanded Khorana scores (OR = 5 [1.4-23.5]) and 5.8 [1.4-28.2], respectively). Summary/Conclusions: Prospective studies are needed to confirm our results and determine if VWF and ADAMTS13 can be used as predictive markers of VTE in stage III/IV cancer patients. Our results also highlight a role of VWF and ADAMTS13 in the pathophysiology of VTE in cancer

Mechanisms of heparin induced anti-cancer activity in experimental cancer models

Background: Retrospective analyses of clinical trials and prospective clinical studies have suggested that heparins may have an effect on cancer survival. This putative anti-cancer activity of heparins is supported by data from studies in animal tumour models. Objective: To clarify the various potential mechanisms of heparin anti-cancer activity we evaluated the data from pre-clinical studies in which heparins have been tested as anti-cancer therapy. Methods: Pre-clinical studies, published between 1960 and 2005 were assessed. Data were collected on the type and dose of heparin used, duration of exposure to heparin, interval between heparin administration and cancer cell inoculation, and the animal tumour model used. In addition, a distinction was made in the analysis between heparin effects on the primary tumour or on established metastases and effects on the metastatic potential of infused cells. Results: Heparins seemed to affect the formation of metastasis rather than the growth of primary tumours. Chemically modified heparins with no or limited anticoagulant activity also showed anti-metastatic properties. Possible mechanisms to explain the effects on the process of metastases include inhibition of blood coagulation, inhibition of cancer cell-platelet and -endothelial interactions by selectin inhibition and inhibition of cell invasion and angiogenesis. Conclusion: The anti-cancer activity of heparins depends more on inhibition of metastasis formation than on the effects on primary tumour growth. These effects are probably related to both coagulation and non-coagulation dependent factors. For a definitive proof of the anti-cancer activity of heparins in the clinic, prospective randomized trials especially in patients with early metastatic disease or in the adjuvant setting are urgently needed. (c) 2006 Elsevier Ireland Ltd. All rights reserve

Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis

Background Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type.Methods In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526.Findings We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta- analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93–1·06) and a hazard ratio of 1·01 (95% CI 0·96–1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low- molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47–0·71) for venous thromboembolism, 1·27 (0·92–1·74) for major bleeding, and 1·34 (1·19–1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42–0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high.Interpretation Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival.Funding Canadian Institutes of Health Research