Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis.

OBJECTIVE: To maintain living, interactive evidence (LIvE) on the benefits and harms of different treatment options in adults with cancer-associated thrombosis (CAT). METHODS: We have used a novel LIvE synthesis framework to maintain this living, interactive systematic review since September 19, 2018. Randomized controlled trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin for CAT are included in this analysis. Details of LIvE synthesis framework are available at the website https://cat.network-meta-analysis.com. RESULTS: The results are constantly updated as new information becomes available (https://cat.network-meta-analysis.com/CAT.html). The living, interactive systematic review currently includes 4 randomized controlled trials (N=2894). Direct comparisons show that DOACs significantly decrease recurrent venous thromboembolism (VTE) events compared with dalteparin (odds ratio [OR], 0.59; 95% CI, 0.41 to 0.86; I2, 25%) without significantly increasing major bleeding (OR, 1.34; 95% CI, 0.83 to 2.18; I2, 28%). Mixed treatment comparisons show that apixaban (OR, 0.41; 95% credible interval [CrI], 0.16 to 0.95) and rivaroxaban (OR, 0.58; 95% CrI, 0.37 to 0.90) significantly decrease VTE recurrent events compared with dalteparin. Edoxaban significantly increases major bleeding compared with dalteparin (OR, 1.73; 95% CrI, 1.04 to 3.16), and rivaroxaban significantly increases clinically relevant nonmajor bleeding compared with dalteparin and other DOACs. There are no significant differences between DOACs in terms of VTE recurrences and major bleeding. CONCLUSION: DOACs should be considered a standard of care for the treatment of CAT except in patients with a high risk of bleeding. Current evidence favors the use of apixaban for the treatment of CAT among other DOACs. REGISTRATION: Open Science Framework (https://osf.io/dth86).

In cancer-associated VTE, apixaban was noninferior to dalteparin for recurrence and did not increase major bleeding.

SOURCE CITATION: Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020;382:1599-607. 32223112.

Lung Cancer Screening with Low-Dose CT: a Meta-Analysis.

BACKGROUND: Randomized controlled trials have evaluated the efficacy of low-dose CT (LDCT) lung cancer screening on lung cancer (LC) outcomes. OBJECTIVE: Meta-analyze LDCT lung cancer screening trials. METHODS: We identified studies by searching PubMed, Google Scholar, the Cochrane Registry, ClinicalTrials.gov , and reference lists from retrieved publications. We abstracted data on study design features, stage I LC diagnoses, LC and overall mortality, false positive results, harm from invasive diagnostic procedures, overdiagnosis, and significant incidental findings. We assessed study quality using the Cochrane risk-of-bias tool. We used random-effects models to calculate relative risks and assessed effect modulators with subgroup analyses and meta-regression. RESULTS: We identified 9 studies that enrolled 96,559 subjects. The risk of bias across studies was judged to be low. Overall, LDCT screening significantly increased the detection of stage I LC, RR = 2.93 (95% CI, 2.16-3.98), I2 = 19%, and reduced LC mortality, RR = 0.84 (95% CI, 0.75-0.93), I2 = 0%. The number needed to screen to prevent an LC death was 265. Women had a lower risk of LC death (RR = 0.69, 95% CI, 0.40-1.21) than men (RR = 0.86, 95% CI, 0.66-1.13), p value for interaction = 0.11. LDCT screening did not reduce overall mortality, RR = 0.96 (95% CI, 0.91-1.01), I2 = 0%. The pooled false positive rate was 8% (95% CI, 4-18); subjects with false positive results had < 1 in 1000 risk of major complications following invasive diagnostic procedures. The most valid estimates for overdiagnosis and significant incidental findings were 8.9% and 7.5%, respectively. DISCUSSION: LDCT screening significantly reduced LC mortality, though not overall mortality, with women appearing to benefit more than men. The estimated risks for false positive results, screening complications, overdiagnosis, and incidental findings were low. Long-term survival data were available only for North American and European studies limiting generalizability.

Screening Coverage Needed to Reduce Mortality from Prostate Cancer: A Living Systematic Review.

INTRODUCTION: Screening for prostate cancer remains controversial because of conflicting results from the two major trials: The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). OBJECTIVE: Meta-analyze and meta-regress the available PSA screening trials. METHODS: We performed a living systematic review and meta-regression of the reduction in prostate cancer mortality as a function of the duration of screening provided in each trial. We searched PubMed, Web of Science, the Cochrane Registry, and references lists from previous meta-analyses to identify randomized trials of PSA screening. We followed PRISMA guidelines and qualified strength of evidence with a GRADE Profile. RESULTS: We found 6 trials, but excluded one that also screened with trans-rectal ultrasound. We considered each ERSPC center as a separate trial. When pooling together all 11 trials we found no significant benefit from screening; however, the heterogeneity was 28.2% (95% CI: 0% to 65%). Heterogeneity was explained by variations in the duration of serial screening (I2 0%; 95% CI: 0% to 52%). When we analyzed the subgroup of trials that added more than 3 years of screening (range 3.2 to 3.8) we found a significant benefit for screening with risk ratio 0.78 (95% CI 0.65-0.94; I2 = 0%; 95% CI: 0% to 69%) and a number needed to invite for screening of 1000. We downgraded the quality of evidence to moderate due to our retrospective identification of subgroups and limited data on control group screening. CONCLUSIONS: Adequate duration of screening reduces mortality from prostate cancer. The benefit, while small, compares favorably with screening for other cancers. Our projections are limited by the moderate quality of evidence.

Variations in pharmacology of beta-blockers may contribute to heterogeneous results in trials of perioperative beta-blockade.

BACKGROUND: Randomized controlled trials and meta-analyses provide conflicting guidance on the role of beta-adrenergic receptor blockers (beta-blockers) in reducing perioperative complications. We hypothesize that variability in trial results may be due in part to heterogeneous properties of beta-blockers. First, we propose that the extent of beta-blocker metabolism by cytochrome P-450 and the time available to titrate the dosage before surgery (titration time) may interact; dependence on P-450 may be most harmful when titration time is short. Second, beta-blockers vary in their selectivity for the beta-1 receptor and reduced selectivity may contribute to cerebral ischemia. METHODS: We used meta-analysis and meta-regression of existing trials to explore the role of these pharmacological properties. RESULTS: We found that both of these pharmacological factors are significantly associated with reduced efficacy of beta-blockers. CONCLUSIONS: Pharmacological properties of beta-blockers may contribute to heterogeneous trial results. Many trials have used metoprolol, which is extensively metabolized by cytochrome P450 and is less selective for the beta-1 receptor. For these two reasons, the efficacy of metoprolol to prevent perioperative cardiac complications should be compared with the efficacy of other beta-blockers.