An answer to “anticoagulant treatment of cancer‐associated venous thromboembolism: Interpreting real‐world data with caution”
Authors: Michael B. Streiff, Dejan Milentijevic, Keith McCrae, Daniel Yannicelli, Dominique Lejeune, Winnie W. Nelson, François Laliberté, Concetta Crivera, Patrick Lefebvre, Jeff Schein, Alok A. Khorana
Journal: American Journal of Hematology (2018)

We have read with interest the Correspondence by Mette Søgaard and Peter Brønnum Nielsen on our “Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer” study recently published in the American Journal of Hematology.1 The authors went to great lengths to mention that the choice of pairwise weighted analyses corresponds to conducting three randomized controlled trials, with different sets of inclusion and exclusion criteria per pair of treatments. They also emphasize that the comparative effectiveness and safety of the three treatment regimens could instead have been compared with a three-arm approach, using an analytic strategy that accounted for multilevel treatments. As Drs. Søgaard and Brønnum Nielsen noted, the inverse probability of treatment (IPT) weighting method that was used is an appropriate analytic approach, since this allows for the estimation of the average treatment effect in the population (ie, warfarin users, rivaroxaban users, and low-molecular-weight heparin [LMWH] users). We would also like to point out that trials where the efficacy and safety of anticoagulant therapies among patients with cancer was evaluated so far have only presented pairwise comparisons (CLOT, CATCH, and SELECT-D trials),2-4 and in that regard findings from our study would be more relatable to the trials' results. Drs. Søgaard and Brønnum Nielsen mention that this complicates the comparison of the three treatment regimens and that the interpretation is not as straightforward as it may seem when reading the article. To alleviate these concerns, we present in this answer to their Correspondence the unweighted baseline characteristics of the three cohorts (see Supporting Information Table S1), as well as analyses of VTE recurrence and major bleeding events including the three cohorts in the same Cox proportional hazards regression model (see Table 1) in a three-arm fashion. We reported both unadjusted and adjusted hazard ratios (HRs), using the same set of covariates in the multivariable model that was used for the IPT weights in our original study. The results hold very well whether we used our original IPT weighting approach or a three-arm method. In fact, our original finding was a HR of 0.72 95%CI (0.52-0.95) with a P-value of .024 for the rivaroxaban versus LMWH comparison,1 while in the three-arm method the corresponding HR is 0.73 95%CI (0.57-0.92) with a P-value of .012. For the warfarin versus LMWH comparison, the HR was not significant at 1.02, and in the three-arm model corresponding HR is not significant at 0.94. Even though the models for VTE recurrence and major bleeding events are presented with LMWH as the reference, the HRs of rivaroxaban and warfarin also held the same relationship as in our original study. We also note that the IPT weighting method we used has minimal effect on the magnitude of the rates (%) of events. The interpretation of major bleeding results remains in line with our original study findings as well. The two methods thus produced very consistent and similar results, which demonstrates the robustness of the methodology we used. Drs. Søgaard and Brønnum Nielsen mention next that the magnitude of event rates is high, and refer to previous trials and real-world data to question the generalizability of the findings. We would like to explain how this concern may be overdrawn. We presented findings using the same design and method at The American Society of Hematology (ASH) 2017, but on a younger commercial population using the Truven MarketScan databases.5 The VTE rates of events found in the commercial population were approximately 30%-50% lower compared with those of our current article where we used Humana data, a predominantly Medicare population.1 It must also be noted that the 6-month rates of VTE recurrences found in the younger population (~12% for LMWH, ~9.5% for warfarin, and ~8.5% for rivaroxaban) are within similar range to those found in the CATCH (7.2% for LMWH and 10.5% for warfarin), CLOT (9.0% for LMWH and 17.0% for warfarin), and SELECT-D trials (11.0% for LMWH and 4.0% for rivaroxaban).2-5 These similarities between the findings we presented at ASH5 and the CLOT, CATCH, and SELECT-D trials can possibly be explained by the similar demographic between these populations, especially in terms of age. More precisely, the mean age of the commercial population evaluated in our study was approximately 62 years old, while mean ages of patients were approximately 59 and approximately 62 years old in CATCH and CLOT trials, respectively; and the median age was 67 (range: 22-87) in the SELECT-D trial (mean age not reported).2-5 Conversely, it suggests that the higher rates found in our analyses using Humana data may be in part explained by the older population (~72-73 years old) studied.1 Lastly, we acknowledged that missing information on mortality is a limitation in this study, as it was mentioned in the article. This could have led to potential overestimation of cumulative probability of events, but not HR, as we do not anticipate that mortality would be significantly different among the cohorts considering that we balanced cohorts on over 20 characteristics including cancer types. In the analyses conducted on a younger commercial population mentioned above, mortality was not evaluated either and the rates reported were in comparable range with the trials. Consequently, age and comorbidities are likely to play a significant role in the explanation for the higher rates we observed in our original study (Streiff et al.). We would like to thank Dr. Søgaard and Dr. Brønnum Nielsen for reviewing our article. Their feedback incited us to broaden the scope of our analyses, which yielded results in line with our original findings. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.