It is unclear if direct oral anticoagulants (DOACs) are effective and safe alternatives to low-molecular-weight heparin (LMWHs) for the treatment of cancer-associated venous thromboembolism (VTE). We ...aim to synthesize existing literature that compared DOACs versus LMWHs in this high-risk population.
We conducted a systematic review using EMBASE, MEDLINE and CENTRAL for all observational studies and randomized controlled trials (RCTs) (PROSPERO: CRD42017080898). Two authors independently reviewed study eligibility, extracted data, and assessed bias. Primary outcomes included 6-month recurrent VTE and major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB) and mortality.
We screened 426 articles, reviewed 25 in full-text, and selected 13 and 2 for qualitative and quantitative synthesis, respectively. Based on a meta-analysis of the 2 RCTs, DOACs had lower 6-month recurrent VTE (42/725) when compared to LMWH (64/727) (RR: 0.65 (0.42–1.01)). However, DOACs had higher major bleeding (40/725) when compared to LMWH (23/727) (RR 1.74 (1.05–2.88)). Similarly, CRNMB was higher (RR 2.31 (0.85–6.28)) for patients receiving DOACs. There was no difference in mortality (RR 1.03 (0.85–1.26)). Observational studies were heterogeneous with high risks of bias but showed recurrent VTE rates consistent with the meta-analysis.
DOACs were more effective than LMWHs to prevent recurrent VTE but were associated with a significantly increased risk of major bleeding as well as a trend toward more CRNMB. The absolute risk differences were small (2–3%) for both primary outcomes and may reflect better compliance with DOACs than LMWHs.
•LMWHs have been the treatment of choice for cancer associated VTE.•DOACs are more effective than LMWHs to prevent recurrent VTE in cancer patients.•DOACs are associated with a higher risk of major bleeding compared to LMWHs.•Effectiveness and safety may reflect better compliance with DOACs compared to LMWHs.
Patients with cancer have a high risk of venous thromboembolism (VTE) and about one-half of these events are incidentally detected. The prognosis of incidental VTE appears to be similar to ...symptomatic events, with comparably high rates of recurrent VTE in this patient population. In the absence of major contraindications, anticoagulant treatment with low-molecular-weight heparin for 3 to 6 months is generally recommended for incidental proximal deep vein thrombosis as well as for incidental pulmonary embolism that involves multiple subsegmental or more proximal pulmonary arteries. The decision of whether to extend treatment beyond 3 to 6 months should be evaluated on a case-by-case basis after periodic reassessment of the risks factors for bleeding and recurrent VTE while also taking into account patient preferences. The clinical relevance of a single incidental subsegmental pulmonary embolism without concomitant deep vein thrombosis is uncertain and either a watchful approach or a shorter course of anticoagulation to minimize the bleeding risk may also be considered. Preliminary evidence suggests that anticoagulation treatment may be beneficial for cancer patients with incidental distal deep vein thrombosis or incidental splanchnic vein thrombosis.
Case-fatality rates are important for assessing the risks and benefits of anticoagulation in patients with venous thromboembolism (VTE).
To summarize case-fatality rates of recurrent VTE and major ...bleeding events during anticoagulation and recurrent VTE after anticoagulation.
MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and all evidence-based medicine reviews in the Ovid interface through the second quarter of 2008.
69 articles (13 prospective cohort studies and 56 randomized, controlled trials) that reported on patients with symptomatic VTE who received anticoagulation therapy for at least 3 months and on the rate of fatal recurrent VTE and fatal major bleeding.
Two reviewers independently extracted data onto standardized forms.
During the initial 3 months of anticoagulation, the rate of recurrent fatal VTE was 0.4% (95% CI, 0.3% to 0.6%), with a case-fatality rate of 11.3% (CI, 8.0% to 15.2%). The rate of fatal major bleeding events was 0.2% (CI, 0.1% to 0.3%), with a case-fatality rate of 11.3% (CI, 7.5% to 15.9%). After anticoagulation, the rate of fatal recurrent VTE was 0.3 per 100 patient-years (CI, 0.1% to 0.4%), with a case-fatality rate of 3.6% (CI, 1.9% to 5.7%).
Estimates come from heterogeneous trial and cohort populations and are not derived from patient-level longitudinal data. Differences in case-fatality rates during and after anticoagulation may be attributable to unmeasured patient characteristics.
The case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment. The case-fatality rate of recurrent VTE decreases after completion of the initial period of anticoagulation. When combined with absolute rates of recurrent VTE and major bleeding events, case-fatality rates provide clinicians with a surrogate measure of mortality to balance the risks and benefits of anticoagulant therapy in patients with VTE.
Canadian Institute for Health Research and Heart and Stroke Foundation of Ontario.
AbstractObjectivesTo determine the rate of a first recurrent venous thromboembolism (VTE) event after discontinuation of anticoagulant treatment in patients with a first episode of unprovoked VTE, ...and the cumulative incidence for recurrent VTE up to 10 years.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials (from inception to 15 March 2019).Study selectionRandomised controlled trials and prospective cohort studies reporting symptomatic recurrent VTE after discontinuation of anticoagulant treatment in patients with a first unprovoked VTE event who had completed at least three months of treatment.Data extraction and synthesisTwo investigators independently screened studies, extracted data, and appraised risk of bias. Data clarifications were sought from authors of eligible studies. Recurrent VTE events and person years of follow-up after discontinuation of anticoagulant treatment were used to calculate rates for individual studies, and data were pooled using random effects meta-analysis. Sex and site of initial VTE were investigated as potential sources of between study heterogeneity.Results18 studies involving 7515 patients were included in the analysis. The pooled rate of recurrent VTE per 100 person years after discontinuation of anticoagulant treatment was 10.3 events (95% confidence interval 8.6 to 12.1) in the first year, 6.3 (5.1 to 7.7) in the second year, 3.8 events/year (95% confidence interval 3.2 to 4.5) in years 3-5, and 3.1 events/year (1.7 to 4.9) in years 6-10. The cumulative incidence for recurrent VTE was 16% (95% confidence interval 13% to 19%) at 2 years, 25% (21% to 29%) at 5 years, and 36% (28% to 45%) at 10 years. The pooled rate of recurrent VTE per 100 person years in the first year was 11.9 events (9.6 to 14.4) for men and 8.9 events (6.8 to 11.3) for women, with a cumulative incidence for recurrent VTE of 41% (28% to 56%) and 29% (20% to 38%), respectively, at 10 years. Compared to patients with isolated pulmonary embolism, the rate of recurrent VTE was higher in patients with proximal deep vein thrombosis (rate ratio 1.4, 95% confidence interval 1.1 to 1.7) and in patients with pulmonary embolism plus deep vein thrombosis (1.5, 1.1 to 1.9). In patients with distal deep vein thrombosis, the pooled rate of recurrent VTE per 100 person years was 1.9 events (95% confidence interval 0.5 to 4.3) in the first year after anticoagulation had stopped. The case fatality rate for recurrent VTE was 4% (95% confidence interval 2% to 6%).ConclusionsIn patients with a first episode of unprovoked VTE who completed at least three months of anticoagulant treatment, the risk of recurrent VTE was 10% in the first year after treatment, 16% at two years, 25% at five years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death. These estimates should inform clinical practice guidelines, enhance confidence in counselling patients of their prognosis, and help guide decision making about long term management of unprovoked VTE.Systematic review registrationPROSPERO CRD42017056309.
Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear.
In this open-label, ...noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.
Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval CI, 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).
Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).
Immune checkpoint inhibitors (ICIs) target programmed cell death (PD) 1 receptor and its ligand PD-L1, and have become an integral part of treatment regimens in many cancers including lung cancer, ...renal cell carcinoma, melanoma, and more. Cancer is associated with a significantly increased risk of venous thromboembolism compared to non-cancer patients, and the risks increase further with anticancer therapies including ICIs. Cancer-associated thrombosis can lead to hospitalizations, delayed cancer treatment, and mortality. While thrombosis was not reported as a major complication in initial clinical trials leading to the approval of ICIs, emerging evidence from post-marketing studies revealed concerning risks of thrombosis in patients receiving ICIs. However, results remained heterogenous given differences in study designs and populations. Recent studies also showed that C-reactive protein dynamics might be an easily accessible biomarker for thrombosis and disease response in this population. In addition, early findings indicated that a commonly used anticoagulant for cancer-associated thrombosis, factor Xa inhibitors, might have potential synergistic antitumor effects when combined with ICIs. Herein we will review the current literature on the incidence, risk factors, and management of thrombosis in patients with cancer receiving ICIs. We aim to provide valuable information for clinicians in managing these patients.
Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic ...review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.
Venous thromboembolism (VTE) is a highly prevalent complication of malignancy with emerging changes in incidence, diagnosis and treatment paradigms. This manuscript, initiated by the Anticoagulation ...Forum, provides clinical guidance based on existing guidelines and consensus expert opinion where guidelines are lacking. We address a) the appropriate workup to search for occult malignancy in patients with idiopathic VTE, b) identification of high-risk cancer patients for primary thromboprophylaxis, c) the appropriate immediate and long-term treatment for people with cancer diagnosed with acute thromboembolism, d) the appropriate duration of anticoagulation and e) the appropriate treatment strategy in patients with recurrent VTE on anticoagulation. Areas of controversy and future directions in this field are highlighted.
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