Page 281 - Haematologica May 2020

Risk stratification of recurrent venous thromboembolism in patients with cancer-associated VTE
VTE as opposed to correct classification. If patients were classified a priori by risk categories (i.e. “high-risk”, “low- risk”) similar to how a diagnostic test would be reported as “disease”, or “no disease”, it is very likely that estimates of intrinsic properties of the Ottawa score would improve. Furthermore, when considering our meta-analysis across each sum of points, we could demonstrate a dose-effect relationship, either continuous (original score) or stepwise (modified score), which confirmed the accuracy of the risk classification of the Ottawa scores.
The accuracy of the modified Ottawa score to identify patients at low risk for VTE recurrence has a potential major therapeutic impact that should be considered for implementation into daily practice. The low 2.2% risk of recurrent VTE in this patient population closely mirrors the recurrent risk of the general VTE population21,22 (refer to DOAC trials). In this setting, the potential advantages of LMWH over oral anticoagulation are clearly counterbal- anced by their cost, their negative impact on quality of life, and the expected low absolute risk reduction of recur- rent VTE (<2% based on a 50% relative risk reduction).23,24 The use of oral anticoagulants in low-risk patients is, therefore, clinically relevant and could be systematically considered as first line in this specific risk group. In con- trast, 49.3% of the patients were classified in the high-risk group by the original Ottawa score. The unacceptable 18.6% estimated rate of recurrent VTE, despite anticoagu- lant treatment, in this group warrants the urgent develop- ment of new therapeutic strategies.
Strengths of our study include its comprehensiveness and the large number of patients included; however, we acknowledge several limitations. First, there was a signifi- cant heterogeneity between studies and some publication bias, particularly in validation studies of the modified score. Nevertheless, most of the studies were of good quality. A major source of heterogeneity was the large dif- ference in incidence rates of recurrent VTE across the stud- ies. Most datasets were old and included patients receiv- ing out-dated cancer therapies. These therapies may have exposed patients to higher risk of recurrent VTE, leading to an overestimation of the current risk. However, the most recent study using the original or modified scores reported an overall recurrence rate of VTE of 9.4 and 8.4%, respectively, which remains high and clinically rel-
evant.15,18 Specific center-related factors that could also potentially affect recurrence-rate of VTE include academic centers, age of included patients and their socio-economic level, number of comorbidities, higher stage disease, his- tory of VTE, and ethnicity. The second limitation of our study was we were unable to account for the type of anti- coagulation used. None of the studied patients were treat- ed with a direct oral anticoagulant. Data on exposure to LMWH or vitamin K antagonist was not available in any of the identified studies. In the derivation and in some of the validation studies, the type of anticoagulation was not a significant predictor for VTE recurrence. However, among all randomized trials, only one showed the superi- ority of LMWH over vitamin K antagonists to treat cancer- associated VTE.25 Third, we could not assess the impor- tance of other risk factors for VTE recurrence (e.g. inter- ruption of anticoagulants for an invasive procedure, age, etc.) during follow up. However, the Ottawa scores were derived without accounting for these confounders and appeared to accurately classify patients. Fourth, patients classified by the original score in the low-risk category had an estimated rate of VTE recurrence of 7.4%, which can- not be considered as low. However, when the score was initially derived, the objective was to identify patients with an a priori risk for VTE recurrence during anticoagu- lation of <7%. In that instance, our data confirm the accu- racy of the original score.
In conclusion, the Ottawa score, either in its original or modified form, is a useful tool to stratify the 6-month risk for VTE recurrence during anticoagulation in patients with cancer-associated VTE. Specifically, the original and mod- ified Ottawa score can accurately identify patients with cancer-associated VTE at high and low risk of recurrent events, respectively. There is an urgent need for the devel- opment of new therapeutic strategies to prevent recurrent VTE in high-risk patients. The original score is an accurate tool to define inclusion criteria of future studies.
Funding
Dr. Khorana acknowledges additional research support from the Sondra and Stephen Hardis Chair in Oncology Research and the National Heart, Lung and Blood Institute (Consortium Linking Oncology with Thrombosis - U01HL143402; R34 HL127156).
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