Anticoagulación para el tratamiento a largo plazo de la tromboembolia venosa en personas con cáncer
References
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en curso
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
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| Study characteristics | ||
| Methods | Multicenter randomized double‐blind trial | |
| Participants | 169 (3.1%) participants with active cancer at baseline with objectively confirmed symptomatic proximal DVT or PE, or both from 358 centers in 28 countries Mean age 65.3 years, 58.5% male, 1/3 had metastatic disease. Most common cancer sites were prostate, breast, colon, bladder and lung | |
| Interventions | Intervention: apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily) for a total of 6 months Control: enoxaparin (1 mg/kg twice daily for at least 5 days) and warfarin (target INR 2‐3) starting day 2 of enoxaparin for a total of 6 months Discontinued treatment: not reported for subgroup of participants with active cancer | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: echo‐doppler for DVT and spiral CT scan for PE | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was performed with the use of an interactive voice‐response system" |
| Allocation concealment (selection bias) | Low risk | Quote: "interactive voice‐response system" Comment: Definitely concealed |
| Blinding of participants and personnel (performance bias) | Low risk | Quote: "AMPLIFY was a randomised, double‐blind trial." Comment: definitely blinded |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All efficacy and safety outcomes were adjudicated by an independent committee blinded to treatment assignment." Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup reported comment: probably complete follow‐up |
| Free of selective reporting? | Low risk | Study not registered. All outcomes listed in the protocol and methods section of this study were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit |
| Study characteristics | ||
| Methods | Multinational, randomized, investigator‐initiated, open‐label, non‐inferiority trial. | |
| Participants | 1155 patients with active cancer from 119 centers in 9 European countries, Israel and the United States. Mean age 67.2 years, 49.2% male, 68% had metastatic disease, 9.2% had previous VTE. Both solid and hematological malignancy. The most frequent solid tumours were: colorectal (about 20%), lung (about 17%) and breast (about 13%). | |
| Interventions | Intervention: Apixaban (10 mg twice daily for 7 days and 5 mg twice daily) for a total of 6 months Control: Dalteparin (200IU per kilogram of body weight once daily for the fist months, after which the dose was reduced to 150IU per kilogram daily). Discontinued treatment: 38/ 576 (6.6%) in the intervention arm and 48/579 (8.3%) | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: CT pulmonary angiography. Diagnostic test for DVT/PE: For DVT ultrasonography, venography, CT venography, or MR venography. For PE CT pulmonary angiography/angiogram or VQ scan. | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote:"Randomization was centrally performed through an interactive online system and stratified according to..." |
| Allocation concealment (selection bias) | Low risk | Quote:"Randomization was centrally performed through an interactive online system and stratified according to..." |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "This trial was a multinational, randomized, controlled, investigator‐initiated, open‐label, noninferiority trial with blinded adjudication of the outcomes" Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions) |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "This trial was a multinational, randomized, controlled, investigator‐initiated, open‐label, noninferiority trial with blinded adjudication of the outcomes |
| Incomplete outcome data (attrition bias) | Low risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (24/585 (4.1%)) and event rate (135/585 (24%)) for the main outcome‐mortality. Similary for the control arm: rate of participants with missing data (17/585 (3%)) and event rate (153/568 (27%)). |
| Free of selective reporting? | Low risk | All outcomes listed in the methods section of this study were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit. |
| Study characteristics | ||
| Methods | Randomized trial (abstract) | |
| Participants | 199 participants with cancer with DVT 17 dropouts, 182 participants completed study | |
| Interventions | Intervention: enoxaparin 100 IU/kg twice daily × 3 months Control: coumadin (target INR 3) × 3 months Discontinued treatment: 17/199 (8.5%) in both arms | |
| Outcomes | Duration of follow‐up for the following outcomes: 3 months
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: ultrasound | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomised outpatient trial" Comment: probably generated sequence randomly |
| Allocation concealment (selection bias) | High risk | Not reported Comment: probably not done |
| Blinding of participants and personnel (performance bias) | High risk | Not reported (oral vs SC intervention) Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Not reported Comment: probably not blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiologic outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | High risk | Comment: judgment based on comparison between rate of participants with missing data (17/199 (8.5%)) and event rate for mortality 1/185 (0.5%) and for major outcome 19/185 (10%) across both arms |
| Free of selective reporting? | High risk | Quote: "in the OC [oral coumadin] group 14 subjects (16.3%) experienced one major outcome event compared with 5 patients (5.2%) out of 96 in the LMWH" Outcomes mentioned in the methods section (DVT, PE, major bleeding) not reported in the results section |
| Free of other bias? | High risk | Study not reported as stopped early for benefit. The full‐text of the study was never published. |
| Study characteristics | ||
| Methods | Randomized clinical trial | |
| Participants | 102 participants with active cancer with DVT, PE, or both 85% Caucasian, mean age 64 years, 46% male, 8.7% had previous VTE | |
| Interventions | Intervention: enoxaparin 1 mg/kg twice daily × 5 days followed by 1.0‐1.5 mg/kg daily × 175 days (group 1a); enoxaparin 1.5 mg/kg daily × 175 days (group 1b) Control: enoxaparin for a minimum of 5 days and until achievement of a stable INR 2‐3 on oral warfarin begun on day 2 of enoxaparin and continued for a total of 180 days of anticoagulation Cointervention: chemotherapy, radiation therapy, or both (not better specified) Discontinued treatment: 43/98 (63%) in the intervention arm and 21/34 (61%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: 1 year
Diagnostic test for DVT/PE: not reported | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomly allocated" Comment: probably generated sequence randomly |
| Allocation concealment (selection bias) | High risk | Not reported Comment: probably not done |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label trial Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Open‐label trial Comment: probably not blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | Low risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (15/68 (22%)) and event rate (22/53 (41%)) for the main outcome‐mortality. Similary for the control arm: rate of participants with missing data (2/34 (6%)) and event rate (11/32 (34%)). |
| Free of selective reporting? | Low risk | Study not registered and no published protocol identified. All relevant outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit |
| Study characteristics | ||
| Methods | Randomized clinical study. | |
| Participants | 138 particpants with active cancer and acute VTE from the oncology outpatient clinic of Beni‐Suef University hospital Egypt. | |
| Interventions | Intervention: Apixaban 10 mg twice daily dose for seven days followed by apixaban 5mg twice daily. Apixaban dose was adjusted to be 2.5mg twice daily in patients with serum creatinine 1.5 mg/dL, elderly patients 80 years or those with body weight 60 kg. Apixaban 10 mg twice daily for seven days followed by 5 mg twice daily for six months. Control: Enoxaparin (1 mg/kg/SC every 12 h). Discontinued treatment: 4/69 (5.8%) in the intervention arm and 8/69 (11.6%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: venous doppler ultrasound. | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote:" Computer based program (Random number generators) using Math.random". |
| Allocation concealment (selection bias) | High risk | Not reported. Comment: probably not concealed |
| Blinding of participants and personnel (performance bias) | High risk | Not reported. Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions) |
| Blinding of outcome assessment (detection bias) | Low risk | Not reported. Comment: probably not blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | High risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (4/69 (5.7%)) and event rate (3/50 (6%)) for the outcome recurrent VTE. Similary for the control arm: rate of participants with missing data (8/68 (11.6%)) and event rate (5/50 (10%)). |
| Free of selective reporting? | Low risk | All outcomes listed in the methods section of this study were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit. Monocentric study. |
| Study characteristics | ||
| Methods | Randomized clinical trial | |
| Participants | 200 participants with cancer (solid or hematologic) with proximal DVT with or without PE Minimum age 18 years, minimum life expectancy 3 months, 50% men, 19% had previous VTE | |
| Interventions | Interventions: tinzaparin 175 anti‐Xa/kg SC daily for 12 weeks Control: UFH either 5000 U or 80 U/kg for 5 days followed by VKAs (target INR 2‐3) for 12 weeks Discontinued treatment: 1/100 (1%) in the intervention arm and 1/100 (1%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: 12 months
Screening test for DVT/PE: not reported Diagnostic test for recurrent VTE: venography or compression ultrasonography | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "a computer‐derived randomised treatment schedule was used; within the each stratum, the randomised schedule was balanced in blocks of 2 and 4." |
| Allocation concealment (selection bias) | High risk | Not reported Comment: probably not concealed |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label trial Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Adjudication was made by 2 committee members not involved in the patient’s care, and disputes were resolved independently by a third. Members of the committee were unaware of the patients' treatment assignments." Comment: probably yes |
| Incomplete outcome data (attrition bias) | Low risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (1/100 (1%)) and event rate (20/99 (20%)) for the outcome mortality. Similary for the control arm: rate of participants with missing data (1/100 (1%)) and event rate 19/99 (19%)). |
| Free of selective reporting? | Low risk | Study not registered. No published protocol identified but a protocol was clearly mentioned in the discussion. All relevant outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized clinical trial | |
| Participants | 676 participants with active cancer and with DVT, PE, or both; ECOG 1 or 2 Mean age 63 years, 49% male, 11% had history of DVT/PE | |
| Interventions | Intervention: dalteparin 200 IU/kg daily × 1 month followed by 150 IU/kg daily × 5 months Control: dalteparin 200 IU/kg daily × 5‐7 days followed by warfarin or acenocoumarol (target INR 2‐3) × 6 months; 46% of time on target Discontinued treatment: 2/338 (0.5%) in the intervention arm and 2/338 (0.5%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: not reported Diagnostic test for DVT: ultrasonography, venography Diagnostic test for PE: lung scan, angiography, autopsy | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "randomizations was stratified according to the clinical center and centralized at the coordinating and methods center." |
| Allocation concealment (selection bias) | Low risk | Quote: "randomizations was stratified according to the clinical center and centralized at the coordinating and methods center." |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label trial Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "all suspected events were reviewed by a central adjudication committee whose members were unaware of the patient's treatment assignments." Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (2/338 (0.5%)) and event rate (120/336 (38.7%)) for the outcome mortality. Similary for the control arm: rate of participants with missing data 2/338 (0.5%)) and event rate 136/336 (40.4%)). |
| Free of selective reporting? | Low risk | Study not registered and no published protocol identified. All relevant outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Phase III, multinational, concealed, randomized, active‐controlled, open‐label trial with blinded adjudication | |
| Participants | 900 randomized participants (adults with active cancer and acute proximal DVT, PE, or both) Mean age 59%, 40% men, 22% gynecologic cancer | |
| Interventions | Intervention: LMWH (tinzaparin) 175 IU/kg SC once daily for 180 days (almost 6 months) Control: VKA (warfarin) for 6 months, overlapping with tinzaparin 175 IU/kg once daily (first 5‐10 days and until INR > 2 for 2 consecutive days) Discontinued treatment: 140/449 (%) in the intervention arm and 172/451 (%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: every 30 days until day 180
Duration of follow‐up for the following outcomes: until 1 month following last dose of study treatment
Screening test for DVT/PE: not reported Diagnostic test for DVT: ultrasonography, venography, CT venography or magnetic resonance venography Diagnostic test for PE: ventilation/perfusion scintigraphy, standard pulmonary angiography or CT | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "treatment assignment was planned according to a computer‐generated randomisation schedule 1:1 in a ratio." |
| Allocation concealment (selection bias) | Low risk | Quote: "concealed until individual randomisation using an interactive voice‐response system" |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label study Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Members of a central, independent adjudication committee, who were unaware of the study treatment assignments, reviewed and adjudicated all suspected cases of recurrent VTE, heparin‐induced thrombocytopenia (HIT), bleeding events, and causes of death." |
| Incomplete outcome data (attrition bias) | High risk |
Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (33/449 (7.3%)) and event rate (6.9%)) for the outcome recurrent VTE. Similary for the control arm: rate of participants with missing data (50/451 (11%)) and event rate 136/336 (10%)) |
| Free of selective reporting? | High risk | Protocol available. Not all outcomes listed in the protocol were reported on (such as other assessments: post‐thrombotic syndrome, HRQoL, VTE risk factors, healthcare resource utilization). |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized clinical trial | |
| Participants | 35 participants with known malignancy; treated for symptomatic DVT of the lower limbs Minimum age 18 years, mean age 65.7 years | |
| Interventions | Intervention: nadroparin 1.025 AXa IU/10 kg twice daily for 3 days then randomised to nadroparin 1.025 antiXa IU/10 kg twice daily After the 3rd month, nadroparin was switched to once daily Control: nadroparin 1.025 AXa IU/10 kg twice daily for 3 days then randomised to acenocoumarol (target INR 2‐3) for 3‐6 months. . 68% of INR values were on target Discontinued treatment: not reported | |
| Outcomes | Duration of follow‐up for the following outcomes: 12 months
Screening test for DVT/PE: not reported Diagnostic test for DVT: duplex scan examination | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were allocated at random on third day to receive a LMWH or an OA [oral anticoagulant]" Comment: Probably generated sequence randomly |
| Allocation concealment (selection bias) | High risk | Not reported Comment: probably not concealed |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "It was not possible to use a double design for the study" Comment: definitely not blinded; knowledge of the assigned intervention may lead to differential behaviours across intervention groups (for example, differential drop‐out, differential cross‐over to an alternative intervention, or differential administration of co‐interventions) |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "the final allocation of all potential outcome events, including deaths, was made by an independent panel of physicians" Comment: probably blinded |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup was reported Comment: assumed complete follow‐up |
| Free of selective reporting? | Low risk | Study not registered and no published protocol identified. All relevant outcomes listed in the methods section are reported on in the results section |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized controlled trial (abstract) | |
| Participants | 46 participants with paraneoplastic DVT | |
| Interventions | Intervention: Fixed‐dose dabigatran (according to individual creatinine clearance) Control: Adjusted‐dose acenocoumarol (according to individual INR determined monthly) Discontinued treatment: not reported | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: not reported | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "we randomised" Comment: probably generated sequence randomly |
| Allocation concealment (selection bias) | Unclear risk | Not reported |
| Blinding of participants and personnel (performance bias) | Unclear risk | Not reported |
| Blinding of outcome assessment (detection bias) | Unclear risk | Not reported |
| Incomplete outcome data (attrition bias) | Unclear risk | Not reported |
| Free of selective reporting? | Unclear risk | Study not registered and no published protocol identified |
| Free of other bias? | Unclear risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized, open‐label, invetigator‐initiated, IV phase, multicenter, superiority trial. | |
| Participants | 300 patients from 28 center in the United States. Mean age 64 years; 48% men, 65% had metastatic disease, 36% had DVT at baseline, 40% had PE at baseline, 6,5% had previous VTE. Both solid and hematological malignancy. The most frequent solid tumours were: colorectal (about 16%), lung (about 17%) and pancreatic (about 16%). | |
| Interventions | Intervention: Apixaban 10 mg twice daily for seven days followed by 5 mg twice daily for six months. Control: Dalteparin (200 IU/kg for one month followed by 150 IU/kg once daily) for six months. Discontinued treatment: 20/150 (13.3%) in the intervention arm and 37/150 (24.7%) | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: survillance related imaging Diagnostic test for DVT: duplex ultrasonography and venography and CT or MRI. Diagnostic test for PE: CT, MR, pulmonary angiography or VQ imaging. | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote:"Randomization was performed using an established interactive Web‐based system that is used for all clinical trials conducted through the Mayo Clinic Cancer Center and through the ACCRU infrastructure." |
| Allocation concealment (selection bias) | Low risk | Not reported Comment: probably not concealed |
| Blinding of participants and personnel (performance bias) | High risk | Not reported. Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions) |
| Blinding of outcome assessment (detection bias) | Low risk | Not reported. Comment: probably not blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | High risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (20/150 (13.3%)) and event rate (23/130 (17.7%)) for the outcome mortality. Similary for the control arm: rate of participants with missing data 37/150 (24.6%)) and event rate 15/113 (13.2%)) |
| Free of selective reporting? | Low risk | All outcomes listed in the methods section of this study were reported on in the results section. |
| Free of other bias? | Low risk | Quote:" Study not reported as stopped early for benefit". |
| Study characteristics | ||
| Methods | Randomized clinical trial | |
| Participants | 146 participants with cancer (solid or hematologic; active or in remission but on treatment); with PE, DVT, or both Minimum age 18 years, minimum life expectancy 3 months, mean age 65.5 years; 45% men | |
| Interventions | Intervention: enoxaparin 1.5 mg/kg daily × 3 months Control: enoxaparin 1.5 mg/kg daily × 4 days followed by warfarin (target INR 2‐3) × 3 months; 41% of time on target The continuation and nature of anticoagulant treatment after 3 months were left to the attending physician.
Discontinued treatment: 4/71 (5.6%) in the intervention arm and 4/75 (5.3%) in the control arm | |
| Outcomes | Duration of follow‐up for the following outcomes: 3 and 6 months
Screening test for VTE: radiologic surveillance Diagnostic test for DVT: venography or compression ultrasonography Diagnostic test for PE: pulmonary angiography or ventilation/perfusion scanning | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Treatment allocation was balanced at each center in blocks of 4." |
| Allocation concealment (selection bias) | Low risk | Quote: "randomisation was performed using pre‐sealed treatment boxes." |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label study Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "all potential outcome events were assessed by an independent adjudication committee whose members were unaware of the treatment assignment." Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk |
Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (4/71 (5.6%)) and event rate (11.3%) for the outcome mortality. Similary for the control arm: rate of participants with missing data (4/75 (5.3%)) and event rate (22.7%) |
| Free of selective reporting? | Low risk | Study not registered and no published protocol identified. All relevant outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Subgroup analysis of participants with active cancer in the EINSTEIN‐DVT and EINSTEIN‐PE phase 3 open‐label multicenter trials | |
| Participants | 459 participants with active cancer, symptomatic DVT and PE enrolled from 314 centers in 38 countries Median age 65‐75 years, 56% males, 22% had metastatic disease, 26% received chemotherapy
| |
| Interventions | Intervention: rivaroxaban 15 mg twice daily for 21 days, followed by 20 mg once daily for 3, 6 or 12 months Control: enoxaparin 1 mg/kg twice daily started within 48 hours after randomization and discontinued when the INR was ≥ 2 for 2 days consecutively and the participant had received ≥ 5 days and warfarin or acenocoumarol (adjusted to maintain INR 2‐3) for 3, 6 or 12 months Discontinued treatment: not reported for cancer subgroup | |
| Outcomes | Duration of follow‐up was for the intended treatment period (3, 6 or 12 months) at 1 week, 2 weeks, 1 month and monthly thereafter for the following outcomes:
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: echo‐doppler for DVT and spiral CT scan for PE | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomisation was done separately for participants with deep‐vein thrombosis and pulmonary embolism (with or without deep‐vein thrombosis), with a computerised voice‐response system, and was stratified according to country and the intended treatment duration (3, 6, or 12 months), as decided locally before randomisation." |
| Allocation concealment (selection bias) | Low risk | Quote from protocol: "Allocation to treatment will be done centrally by interactive voice response system for Einstein‐DVT and Einstein‐PE, separately." |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label study Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All suspected outcomes were classified by an independent blinded adjudication committee." Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup was reported. |
| Free of selective reporting? | Low risk | Study registered and published protocol identified. All outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Subgroup analysis of participants with cancer or history of cancer in the HOKUSAI trial Randomized, double‐blind, double‐dummy, multicenter trial | |
| Participants | 208 participants with active cancer at baseline from 439 centers in 37 countries (208 with active cancer prespecified categorization made by study physician at enrolment; 162 with active cancer post‐hoc classification) Mean age 66 years, 50% male, 6% with metastatic disease, 10% receiving systemic cancer‐drug therapy, excludes 77 participants with non‐melanoma skin cancer | |
| Interventions | All participants received initial therapy with open‐label enoxaparin or UFH for ≥ 5 days Intervention: edoxaban 60 mg once per day or 30 mg once per day + dummy warfarin for ≥ 3 months Control: warfarin concurrently started with the study regimen of heparin (adjusted to maintain INR 2‐3) + dummy edoxaban for ≥ 3 months. Enoxaparin was discontinued when the INR was ≥ 2 for 2 days consecutively and the participant had received ≥ 5 days of enoxaparin treatment Initial therapy with open‐label enoxaparin or UFH for ≥ 5 days Discontinued treatment: not reported for the active cancer subgroup | |
| Outcomes | Duration of follow‐up for the following outcomes: 12 months
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: not reported | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "local site study physician or study coordinator did the randomisation using an interactive web‐based system, with stratification according to the qualifying diagnosis (deep‐vein thrombosis or pulmonary embolism), presence or absence of temporary risk factors, and the dose of edoxaban." |
| Allocation concealment (selection bias) | Low risk | Quote: "The investigator provides this information to an interactive telephone and web‐based management system (IXRS; Almac, Yardley, PA, USA), which randomly assigns the participant to the LMWH/edoxaban or standard therapy group, and allocates the appropriate drug supply. The day of randomisation is day 1 of the study." |
| Blinding of participants and personnel (performance bias) | Low risk | Double‐blind trial Comment: definitely blinded |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "central independent adjudication of all suspected outcomes" Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup was reported. |
| Free of selective reporting? | Low risk | Study registered and published protocol identified. All outcomes reported in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized, open‐label, non‐inferiority, multicenter clinical trial | |
| Participants | 1050 people with active cancer from 114 centers in 13 countries with acute symptomatic or incidentally detected DVT or PE Median age 64 years, 51.7% males, 53% had metastatic disease, 72.4% received cancer treatment within previous 4 weeks "anticancer drug therapy (cytotoxic, hormonal, targeted, or immunomodulatory), radiation therapy, surgery, or a combination of these therapies." | |
| Interventions | All patients received initial therapy with LMWH for ≥ 5 days. Duration of treatment: 6‐12 months Intervention: LMWH for ≥ 5 days followed by oral edoxaban 60 mg once daily Control: dalteparin 200 IU per kilogram bodyweight SC once daily for 1 month followed by dalteparin 150 IU per kilogram once daily Discontinued treatment: 48/525 (9.1%) in the intervention arm and 34/525 (6.4%)
| |
| Outcomes | Duration of follow‐up for the following outcomes: 12 months (on day 31 after randomization and months 3, 6, 9 and 12)
Screening test for DVT/PE: "Incidental venous thromboembolism was defined as thromboembolism that was detected by means of imaging tests performed for reasons other than clinical suspicion of venous thromboembolism." Diagnosis test for DVT/PE: "Appropriate diagnostic tests, laboratory tests, or both were required in people with suspected outcome events...aminotransferase and bilirubin levels." | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Randomization was performed with the use of an interactive Web‐based system, with stratification according to whether risk factors for bleeding were present and whether the patient met the criteria to receive a lower dose of edoxaban." |
| Allocation concealment (selection bias) | Low risk | Quote: "Randomization was performed with the use of an interactive Web‐based system, with stratification according to whether risk factors for bleeding were present and whether the patient met the criteria to receive a lower dose of edoxaban." Comment: probably concealed |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "Open label trial" Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "all events were adjudicated by a committee whose members were unaware of the treatment assignments." Comment: probably blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | High risk |
Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (16/525 (3.04%)) and event rate (34/509 (6.7%)) for the outcome recurrent VTE. Similary for the control arm: rate of participants with missing data (59/525 (11.2%)) and event rate (46/507 (9.07%) |
| Free of selective reporting? | Low risk | Study registered and published protocol identified. All outcomes reported in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Randomized trial | |
| Participants | 69 participants with cancer (study subgroup) and symptomatic proximal DVT Minimum age 18 years, mean age 61 years | |
| Interventions | Intervention: tinzaparin SC fixed‐dose 175 IU anti‐Xa per kg once daily for 6 months Control: acenocoumarol 3 mg orally, which was subsequently adjusted to achieve an INR of 2‐3, tinzaparin was given until the INR reached ≥ 2 on 2 consecutive measurements. All participants received tinzaparin SC in a fixed dose of 175 IU anti‐Xa per kg once daily Discontinued treatment: not reported for cancer subgroup | |
| Outcomes | Duration of follow‐up for the following outcomes: 12 months
Screening test for DVT/PE: not reported Diagnostic test for DVT: duplex ultrasonography | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomised to either LMWH group SQ [subcutaneous] or LMWH followed by acenocoumarol" Comment: probably generated sequence randomly |
| Allocation concealment (selection bias) | High risk | Not reported Comment: probably not concealed |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label study Comment: probably not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "the ultrasonic evaluations were performed blindly;" "All objective diagnostic tests were interpreted by specialists who were not involved in the study." Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup reported Comment: assumed complete follow‐up |
| Free of selective reporting? | Low risk | Study was registered (NCT00689520). All relevant outcomes listed on the registration page and the methods section of the published manuscript were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Subgroup analysis of participants with cancer at baseline, diagnosed with cancer during the study, or history of cancer pooled from the RE‐COVER and RE‐COVER II trials Randomized, double‐blind, double‐dummy, multicenter trials | |
| Participants | 221 participants with active cancer at baseline and acute symptomatic proximal DVT or PE, from 228 clinical centers in 29 countries Mean age 63.5 years, 61% male, 8% with metastatic cancer | |
| Interventions | All participants received parenteral anticoagulant (UFH, LMWH or fondaparinux) until the INR or sham INR became ≥ 2 for 2 consecutive days. Intervention: dabigatran fixed‐dose 150 mg twice daily and warfarin‐placebo Control: dose‐adjusted warfarin therapy, after initial parenteral anticoagulation and dabigatran‐placebo Cointervention: "initial treatment was with a parenteral anticoagulant (UFH, LMWH, or fondaparinux) until INR or sham INR became at least 2.0 for two consecutive days." Discontinued treatment: not reported | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months (assessed at 7 days and monthly thereafter)
Screening test for DVT/PE: not reported Diagnosis test for DVT/PE: not reported | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "We used a computer generated randomisation scheme with variable block sizes" (from main study RECOVER‐I). "Patients were randomised by use of an interactive voice response system and a computer‐generated randomisation scheme in blocks of 4" (from main Studi RECOVER‐II). |
| Allocation concealment (selection bias) | Low risk | Quote: "If the patient was enrolled from the RE‐COVER study or the RE‐COVER II study, a point‐of‐care coagulometer with encrypted INR results was used to guide the transition so that the patients and investigators would remain unaware of the initial treatment." |
| Blinding of participants and personnel (performance bias) | Low risk | Double‐blind trial Comment: definitely blinded |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "central adjudication committee" Comment: definitely blinded |
| Incomplete outcome data (attrition bias) | Low risk | Complete follow‐up (correspondence with author) |
| Free of selective reporting? | Low risk | Study registered and published protocol identified. All outcomes reported in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Post hoc analysis in the subgroup of participants with cancer included in the Van Gogh DVT clinical trial randomized, open‐label noninferiority trial | |
| Participants | 284 participants with active cancer having acute symptomatic and objectively confirmed DVT involving the popliteal, femoral, iliac veins or the trifurcation of the calf veins, without symptomatic PE Quote: "no detailed information on cancer type and stage or co‐medication was collected." | |
| Interventions | Intervention: idraparinux 2.5 mg SC once‐weekly × 3 or 6 months according to the decision of treating physician Control: standard treatment: tinzaparin, enoxaparin or intravenous heparin adjusted for the activated partial thromboplastin time ratio (ratio 1.5‐2.5), followed by warfarin or acenocoumarol (INR 2‐3), which was started within 24 hours after randomization. Cointervention: not reported Quote: "A total of 8% of all patients were randomised in the 3‐month arm, and 92% in the 6‐month treatment arm." Quote: "The duration of treatment was similar with a median of 183 days in both groups." 75% of participants completed the study medication Quote: "Of idraparinux recipients 48 patients (22%) stopped the study medication before the end of the study compared to 56 (28%) patients in the standard treatment arm." Discontinued treatment: not reported for subgroup of patients with active cancer | |
| Outcomes | Duration of follow‐up for the following outcomes: 6‐month treatment period plus additional 3‐month follow‐up period (median 183 days in both groups)
Screening test for DVT/PE: not reported Diagnostic test for DVT/PE: none reported in this manuscript, but available from Buller HR, New England Journal of Medicine 2007;357:1094‐104 Diagnostic testing for PE: spiral computed tomography, pulmonary angiography Diagnostic testing for DVT: ultrasonography, venography | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "After giving written informed consent, patients were randomly assigned to receive either idraparinux or standard therapy with the use of a computerized voice‐response system" (from Buller HR, New England Journal of Medicine 2007;357:1094‐104). |
| Allocation concealment (selection bias) | Low risk | Quote: "After giving written informed consent, patients were randomly assigned to receive either idraparinux or standard therapy with the use of a computerized voice‐response system" (from Buller HR, New England Journal of Medicine 2007;357:1094‐104). |
| Blinding of participants and personnel (performance bias) | High risk | Open‐label study Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "All suspected outcomes were classified by an independent blinded adjudication committee." Comment: definitely blinded; knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | Low risk | No information about follow‐up in the cancer subgroup reported Comment: assumed complete follow‐up |
| Free of selective reporting? | Low risk | Post‐hoc analysis. Study registered and no published protocol identified. All relevant outcomes listed in the methods section were reported on in the results section. |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
| Study characteristics | ||
| Methods | Prospective, randomized, open‐label, multicenter pilot trial | |
| Participants | 406 people with active cancer at baseline with VTE from 58 centers across the UK Mean age 67 years, 53% males, 38% early or locally advanced disease, 59% metastatic disease, 57% receiving chemotherapy, 10% receiving targeted therapy | |
| Interventions | Duration of treatment: 6 months Intervention: rivaroxaban 15 mg twice daily for 3 weeks then 20 mg once daily, for 6 months in total Control: dalteparin 200 IU/kg daily, month 1 and 150 IU/kg, months 2‐6
Discontinued treatment: not reported | |
| Outcomes | Duration of follow‐up for the following outcomes: 6 months
Screening test for DVT/PE: compression ultrasound Diagnosis test for DVT/PE: compression ultrasound | |
| Notes |
| |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "Patients were randomly assigned centrally by telephoning Warwick Clinical Trials Unit. Consenting patients were randomly assigned at a one‐to‐one ratio using a computer‐based minimization algorithm with..."
|
| Allocation concealment (selection bias) | Low risk | Quote: "Patients were randomly assigned centrally by telephoning Warwick Clinical Trials Unit. Consenting patients were randomly assigned at a one‐to‐one ratio using a computer‐based minimization algorithm with..." |
| Blinding of participants and personnel (performance bias) | High risk | Quote: "Trial staff, participants, and investigators were not blinded to treatment allocation" Comment: definitely not blinded; knowledge of the assigned intervention may have led to differential behaviors across intervention groups (e.g. differential dropout, differential cross‐over to an alternative intervention or differential administration of cointerventions). |
| Blinding of outcome assessment (detection bias) | Low risk | Quote: "Trial staff, participants, and investigators were not blinded to treatment allocation" Comment: probably not blinded; however, knowledge of the assigned intervention may not have impacted the assessment of the physiological outcomes (mortality, DVT, PE, bleeding, etc.). |
| Incomplete outcome data (attrition bias) | Low risk | Comment: judgment based on comparison in the intervention arm between rate of participants with missing data (17/203 (8.03%)) and event rate (48/186 (25.8%)) for the outcome mortality. Similary for the control arm: rate of participants with missing data (23/203 (11.3%)) and event rate (56/180 (31.1%) |
| Free of selective reporting? | Low risk | Study registered. All relevant outcomes listed in the methods section were reported on in the results section |
| Free of other bias? | Low risk | Study not reported as stopped early for benefit No other bias suspected |
CT: computer tomography; COI: conflict of interest; DOAC: direct oral anticoagulant; DVT: deep venous thrombosis; ECOG: Eastern Co‐operative Oncology Group; HRQoL: health‐related quality of life; INR: international normalized ratio; ITT: intention to treat; IU: international unit; LMWH: low molecular weight heparin; MPD: missing participants data; PE: pulmonary embolism; SC: subcutaneous; U: unit; UFH: unfractionated heparin; VKA: vitamin K antagonist; VTE: venous thromboembolism.
Characteristics of excluded studies [ordered by study ID]
Jump to:
| Study | Reason for exclusion |
| Not population of interest (surgical setting) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer with CVC without VTE) | |
| Not population of interest (people without cancer) | |
| Not design of interest (review) | |
| Not design of interest (review) | |
| Not design of interest (review) | |
| Outcome data for cancer subgroup not reported | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Outcome data for cancer subgroup not reported | |
| Outcome data for cancer subgroup not reported | |
| Not design of interest (review) | |
| Not population of interest (patients without cancer) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not design of interest (retrospective) | |
| Not design of interest (observational) | |
| Outcome data for cancer subgroup not reported | |
| Not population of interest (people with cancer without VTE) | |
| Not design of interest (review) | |
| Not design of interest (review) | |
| Not design of interest (review) | |
| Not population of interest (people with cancer without VTE) | |
| Outcome data for cancer subgroup not reported | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Outcome data for cancer subgroup not reported | |
| Not population of interest (people with cancer without VTE) | |
| Not intervention of interest (extended treatment) | |
| Not population of interest (none of participants had cancer) | |
| Not intervention of interest (extended treatment) | |
| Not intervention of interest: different duration of interventional drugs | |
| Not population of interest (people with cancer without VTE) | |
| Not design of interest (not an RCT) | |
| Not population of interest (people with cancer without VTE) | |
| Outcome data for cancer subgroup not reported | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) | |
| Not population of interest (people with cancer without VTE) |
DOAC: direct oral anticoagulant; LMWH: low molecular weight heparin; RCT: randomized controlled trial; VTE: venous thromboembolism.
Characteristics of ongoing studies [ordered by study ID]
Jump to:
| Study name | PO‐67 Long‐term treatment for cancer patients with deep vein thrombosis or pulmonary embolism – a randomised controlled trial |
| Methods | Multicenter, multinational, randomized, open‐label trial |
| Participants | Participants with malignancy (all types, solid and hematologic) who had received 6‐12 months of anticoagulation for VTE and had an indication for continuing anticoagulation |
| Interventions | Intervention: weight‐adjusted scheme of LMWH for 6 additional months, 65‐75% of full therapeutic dose Control: VKA for 6 additional months |
| Outcomes | Symptomatic recurrent VTE (DVT and PE), all clinically relevant bleeding (i.e. major bleeding and other clinically relevant non‐major bleeding), all‐cause mortality |
| Starting date | August 2010 |
| Contact information | Professor Pieter W Kamphuisen, telephone: 0031503612943, email: [email protected] |
| Notes | Status as of May 2021: Terminated (Due to slow inclusion of patients)
Funding: University Medical Center Groningen NCT: NCT01164046 |
| Study name | Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients |
| Methods | Randomized open‐label phase III trial |
| Participants | Aged ≥ 18 years with active malignancy and newly diagnosed and objectively confirmed acute VTE |
| Interventions | Drug: rivaroxaban 15 mg twice daily for 21 days, followed by 20 mg once daily over 3 months Drug: LMWH in therapeutic dosage (1‐2 × daily SC) according to standards of the individual study center, using licensed dosages |
| Outcomes | Primary outcome: participant‐reported treatment satisfaction (convenience) with rivaroxaban in the treatment of acute VTE in people with cancer in comparison with the standard treatment with LMWH Secondary outcome: rate of VTE |
| Starting date | March 2016 |
| Contact information | Dr Aysun Karatas, email: aysun.karatas@aio‐studien‐ggmbh.de |
| Notes | Status as of May 2021: Terminated (Recruitment was not as expected).
Funding: AIO‐Studien‐gGmbH NCT02583191 |
| Study name | Cancer associated thrombosis, a pilot treatment study using rivaroxaban (CASTA‐DIVA) |
| Methods | Randomized, open‐label trial |
| Participants | People with cancer aged > 18 years with objectively confirmed symptomatic VTE |
| Interventions | Intervention 1: dalteparin 200 IU/kg SC once daily for 1 month followed by 150 IU/kg SC once daily for 2 months Intervention 2: rivaroxaban 15 mg orally twice daily for 3 weeks followed by 20 mg once daily for 9 weeks |
| Outcomes | Primary outcome: symptomatic DVT, PE at 3 months Secondary outcome: major and clinically significant bleedings during the 3‐month treatment period |
| Starting date | September 2016 |
| Contact information | Guy Meyer, MD, email: [email protected] |
| Notes | Status as of May 2021: completed Funding: Assistance Publique – Hôpitaux de Paris NCT02746185 |
| Study name | A randomized phase II study to compare the safety and efficacy of dalteparin vs. rivaroxaban for cancer‐associated venous thromboembolism (PRIORITY) |
| Methods | Multicenter, randomized, open‐label phase II trial |
| Participants | Aged ≥ 18 years with confirmed locally advanced unresectable or metastatic active cancer and newly diagnosed DVT or PE |
| Interventions | Intervention 1: dalteparin 200 IU/kg SC once daily for 4 weeks followed by 150 IU/kg once daily for 20 weeks Intervention 2: rivaroxaban 15 mg orally twice daily for 3 weeks followed by 20 mg once daily for 21 weeks |
| Outcomes | Primary outcome: rate of clinical relevant bleeding Secondary outcome: total event of bleeding, time to event of bleeding, recurrent VTE |
| Starting date | May 2017 |
| Contact information | Sook Ryun Park, MD, PhD, email: [email protected] |
| Notes | Status as of May 2021: recruiting Funding: Asan Medical Center NCT03139487 |
| Study name | Direct oral anticoagulants (DOACs) versus LMWH ± warfarin for VTE in cancer (CANVAS) |
| Methods | Randomized, open‐label trial |
| Participants | Aged ≥ 21 years with solid tumor cancer, lymphoma or myeloma, diagnosed with VTE < 30 days prior to study enrolment |
| Interventions | Intervention 1: DOAC Intervention 2: LMWH with or without transition to warfarin |
| Outcomes | Primary outcome: cumulative VTE recurrence Secondary outcome: major bleeding, burden of anticoagulation therapy, mortality |
| Starting date | December 2016 |
| Contact information | Deborah Schrag, MD MPH, telephone: 617‐582‐8301, email: [email protected] |
| Notes | Status as of May 2021: compteted Funding: Patient‐Centered Outcomes Research Institute (PCORI) NCT NCT02744092 |
DOAC: direct oral anticoagulant; DVT: deep venous thrombosis; LMWH: low molecular weight heparin; PE: pulmonary embolism; SC: subcutaneous; VTE: venous thromboembolism.
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All‐cause mortality (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.88, 1.12] |
| Analysis 1.1  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months) (main analysis ‐ active cancer) | ||||
| 1.2 All‐cause mortality (time‐to‐event) Show forest plot | 2 | 810 | HR (IV, Random, 95% CI) | 0.94 [0.74, 1.20] |
| Analysis 1.2  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 2: All‐cause mortality (time‐to‐event) | ||||
| 1.3 Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.44, 0.80] |
| Analysis 1.3  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 3: Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer) | ||||
| 1.4 Recurrent venous thromboembolism (time‐to‐event) Show forest plot | 2 | 810 | HR (IV, Random, 95% CI) | 0.49 [0.31, 0.78] |
| Analysis 1.4  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 4: Recurrent venous thromboembolism (time‐to‐event) | ||||
| 1.5 Major bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.55, 2.12] |
| Analysis 1.5  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 5: Major bleeding (up to 6 months) (main analysis ‐ active cancer) | ||||
| 1.6 Minor bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.47, 1.27] |
| Analysis 1.6  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 6: Minor bleeding (up to 6 months) (main analysis ‐ active cancer) | ||||
| 1.7 Thrombocytopenia (up to 6 months) (main analysis‐ active cancer) Show forest plot | 1 | 138 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.52, 1.69] |
| Analysis 1.7  Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 7: Thrombocytopenia (up to 6 months) (main analysis‐ active cancer) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 All‐cause mortality (6‐12 months) Show forest plot | 4 | 1060 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.72, 1.23] |
| Analysis 2.1  Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (6‐12 months) | ||||
| 2.2 Recurrent venous thromboembolism (6‐12 months) Show forest plot | 4 | 1050 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.34, 1.15] |
| Analysis 2.2  Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 2: Recurrent venous thromboembolism (6‐12 months) | ||||
| 2.3 Major bleeding (6‐12 months) Show forest plot | 4 | 1055 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.39, 1.53] |
| Analysis 2.3  Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (6‐12 months) | ||||
| 2.4 Minor bleeding (6‐12 months) Show forest plot | 4 | 1055 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.57, 1.23] |
| Analysis 2.4  Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (6‐12 months) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 All‐cause mortality (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.83, 1.14] |
| Analysis 3.1  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 1: All‐cause mortality (6 months) | ||||
| 3.2 Recurrent VTE (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.45, 0.88] |
| Analysis 3.2  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 2: Recurrent VTE (6 months) | ||||
| 3.3 Major bleeding (6 months) Show forest plot | 5 | 2994 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.83, 1.73] |
| Analysis 3.3  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 3: Major bleeding (6 months) | ||||
| 3.3.1 GI tract cancer | 4 | 854 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.76, 2.84] |
| 3.3.2 Non‐GI tract cancer | 4 | 1853 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.63, 1.73] |
| 3.3.3 GI tract cancer not specified | 1 | 287 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.04] |
| 3.4 Major GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.62, 2.17] |
| Analysis 3.4  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 4: Major GI bleeding (6 months) | ||||
| 3.5 Major upper GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.51, 2.76] |
| Analysis 3.5  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 5: Major upper GI bleeding (6 months) | ||||
| 3.6 Major lower GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.43, 2.80] |
| Analysis 3.6  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 6: Major lower GI bleeding (6 months) | ||||
| 3.7 Major non‐GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.42, 1.68] |
| Analysis 3.7  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 7: Major non‐GI bleeding (6 months) | ||||
| 3.8 Minor bleeding (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 1.58 [1.15, 2.16] |
| Analysis 3.8  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 8: Minor bleeding (6 months) | ||||
| 3.9 Minor GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.41, 4.64] |
| Analysis 3.9  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 9: Minor GI bleeding (6 months) | ||||
| 3.10 Minor upper GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.04, 25.97] |
| Analysis 3.10  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 10: Minor upper GI bleeding (6 months) | ||||
| 3.11 Minor lower GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [0.72, 3.27] |
| Analysis 3.11  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 11: Minor lower GI bleeding (6 months) | ||||
| 3.12 Minor non‐GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 2.37 [1.44, 3.89] |
| Analysis 3.12  Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 12: Minor non‐GI bleeding (6 months) | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 All‐cause mortality (up to 6 months) Show forest plot | 1 | 284 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.78, 1.59] |
| Analysis 4.1  Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months) | ||||
| 4.2 Recurrent VTE (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.16, 1.32] |
| Analysis 4.2  Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 2: Recurrent VTE (up to 6 months) | ||||
| 4.3 Major bleeding (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.35, 3.56] |
| Analysis 4.3  Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (up to 6 months) | ||||
| 4.4 Minor bleeding (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.30, 1.60] |
| Analysis 4.4  Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (up to 6 months) | ||||
Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months) (main analysis ‐ active cancer)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 2: All‐cause mortality (time‐to‐event)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 3: Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 4: Recurrent venous thromboembolism (time‐to‐event)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 5: Major bleeding (up to 6 months) (main analysis ‐ active cancer)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 6: Minor bleeding (up to 6 months) (main analysis ‐ active cancer)
Comparison 1: Low molecular weight heparins (LMWH) versus vitamin K antagonists (VKA), Outcome 7: Thrombocytopenia (up to 6 months) (main analysis‐ active cancer)
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (6‐12 months)
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 2: Recurrent venous thromboembolism (6‐12 months)
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (6‐12 months)
Comparison 2: Direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (6‐12 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 1: All‐cause mortality (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 2: Recurrent VTE (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 3: Major bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 4: Major GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 5: Major upper GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 6: Major lower GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 7: Major non‐GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 8: Minor bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 9: Minor GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 10: Minor upper GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 11: Minor lower GI bleeding (6 months)
Comparison 3: Direct oral anticoagulants (DOAC) versus low molecular weight heparins (LMWH), Outcome 12: Minor non‐GI bleeding (6 months)
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 1: All‐cause mortality (up to 6 months)
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 2: Recurrent VTE (up to 6 months)
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 3: Major bleeding (up to 6 months)
Comparison 4: Idraparinux versus vitamin K antagonists (VKA), Outcome 4: Minor bleeding (up to 6 months)
| Low molecular weight heparin secondary prophylaxis compared to vitamin K antagonist secondary prophylaxis in patients with cancer with venous thromboembolism | |||||
| Population: People with cancer with venous thromboembolism | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with VKA secondary prophylaxis | Risk difference with LMWH secondary prophylaxis | ||||
| All‐cause mortality (main analysis ‐ active cancer) | 1712 | ⊕⊕⊝⊝ | RR 0.99 | Study population | |
| 374 per 1,000 | 4 fewer per 1,000 | ||||
| All‐cause mortality (time‐to‐event) | 1243 | ⊕⊕⊝⊝ | HR 0.94 | Study population | |
| 374 per 1,000 | 18 fewer per 1,000 | ||||
| Recurrent venous thromboembolism (main analysis ‐ active cancer) | 1712 | ⊕⊕⊕⊝ | RR 0.59 | Study population | |
| 124 per 1,000 | 51 fewer per 1,000 | ||||
| Recurrent venous thromboembolism (time‐to‐event) | 1243 | ⊕⊕⊕⊝ | HR 0.49 | Study population | |
| 124 per 1,000 | 61 fewer per 1,000 | ||||
| Major bleeding (main analysis ‐ active cancer) | 1712 | ⊕⊕⊝⊝ | RR 1.09 | Study population | |
| 43 per 1,000 | 4 more per 1,000 | ||||
| Minor bleeding (main analysis ‐ active cancer) | 1712 | ⊕⊝⊝⊝ | RR 0.78 | Study population | |
| 174 per 1,000 | 38 fewer per 1,000 | ||||
| Thrombocytopenia (main analysis‐ active cancer) | 138 | ⊕⊕⊝⊝ | RR 0.94 | Study population | |
| 254 per 1,000 | 15 fewer per 1,000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by one level due to serious risk of bias (allocation concealment unclear in one study, lack of blinding of participants and personnel in all the four studies, high risk of incomplete outcome data in one study, and high risk of selective reporting in one study). 2 Downgraded by one level due to serious imprecision. Confidence interval includes suggests both potential harm and potential benefit. 3 Some concern with lack of blinding of patients and personnel. 4 Some concern with inconsistency. I2= 46% 5 Downgraded by one level due to serious inconsistency (I2= 78%) 6 Downgraded by two levels due to very serious imprecision. Confidence interval includes suggests both potential harm and potential benefit. Low number of events. | |||||
| Direct oral anticoagulant secondary prophylaxis compared to Vitamin K antagonist secondary prophylaxis in patients with active cancer with venous thromboembolism | |||||
| Population: patients with active cancer with venous thromboembolism | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Vitamin K antagonist (VKA) secondary prophylaxis | Risk difference with Direct oral anticoagulant (DOAC) secondary prophylaxis | ||||
| All‐cause mortality | 1060 | ⊕⊕⊝⊝ | RR 0.94 | Study population | |
| 171 per 1,000 | 10 fewer per 1,000 | ||||
| Recurrent venous thromboembolism | 1050 | ⊕⊕⊝⊝ | RR 0.63 | Study population | |
| 49 per 1,000 | 18 fewer per 1,000 | ||||
| Major bleeding | 1055 | ⊕⊕⊝⊝ | RR 0.77 | Study population | |
| 37 per 1,000 | 8 fewer per 1,000 | ||||
| Minor bleeding | 1055 | ⊕⊕⊝⊝ | RR 0.83 | Study population | |
| 127 per 1,000 | 22 fewer per 1,000 | ||||
| Thrombocytopenia ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ |
| Health related quality of life | 8485 | ⊕⊕⊕⊝ | ‐ | Prins 2014 (EINSTEIN DVT‐PE; n=8485 ): "in the general population of the EINSTEIN studies, patient‐reported satisfaction and quality of life was better in the rivaroxaban‐treated patients than in the group treated with enoxaparin and vitamin K antagonist, although we have not yet examined whether this is the same in patients with active cancer. Hence, it can be expected that quality of life will also be improved with rivaroxaban compared with long‐term injected low molecular‐weight heparin." The tool used was validated measure of treatment satisfaction – the Anti‐Clot Treatment Scale (ACTS)) | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Some concern with indirectness (study by Schulman et al (RECOVER I‐II) included patients with a diagnosis of cancer within five years before enrollment), however the weight of these studies was low and heterogeneity was very low. 2 Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential benefit and potential harm. 3 Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential benefit and potential no effect. Low number of events. 4 Downgraded by one level for serious indirectness. The study by Prins and colleagues (Prins 2014 ( EINSTEIN n=8485)) reports health related quality of life for the whole study population, without providing data for the cancer subgroup | |||||
| Direct oral anticoagulant secondary prophylaxis compared to Low molecular weight heparin secondary prophylaxis in patients with cancer with venous thromboembolism | |||||
| Patient or population: patients with cancer with venous thromboembolism | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Low molecular weight heparin (LMWH) secondary prophylaxis | Risk difference with Direct oral anticoagulant (DOAC) secondary prophylaxis | ||||
| All‐cause mortality | 2854 | ⊕⊕⊝⊝ | RR 0.97 | Study population | |
| 248 per 1,000 | 7 fewer per 1,000 | ||||
| Recurrent VTE | 2854 | ⊕⊕⊝⊝ | RR 0.63 | Study population | |
| 87 per 1,000 | 32 fewer per 1,000 | ||||
| Major bleeding | 2994 | ⊕⊕⊝⊝ | RR 1.20 | Study population | |
| 35 per 1,000 | 7 more per 1,000 | ||||
| Major GI bleeding | 1838 | ⊕⊕⊝⊝ | RR 1.16 | Study population | |
| 20 per 1,000 | 3 more per 1,000 | ||||
| Major upper GI bleeding | 1838 | ⊕⊝⊝⊝ | RR 1.18 | Study population | |
| 11 per 1,000 | 2 more per 1,000 | ||||
| Major lower GI bleeding | 1838 | ⊕⊝⊝⊝ | RR 1.10 | Study population | |
| 9 per 1,000 | 1 more per 1,000 | ||||
| Major non‐GI bleeding | 1838 | ⊕⊝⊝⊝ | RR 0.84 | Study population | |
| 19 per 1,000 | 3 fewer per 1,000 | ||||
| Minor bleeding | 2854 | ⊕⊕⊕⊝ | RR 1.58 | Study population | |
| 67 per 1,000 | 39 more per 1,000 | ||||
| Minor GI bleeding | 1495 | ⊕⊝⊝⊝ | RR 1.37 | Study population | |
| 25 per 1,000 | 9 more per 1,000 | ||||
| Minor upper GI bleeding | 1495 | ⊕⊝⊝⊝ | RR 1.03 | Study population | |
| 11 per 1,000 | 0 fewer per 1,000 | ||||
| Minor lower GI bleeding | 1495 | ⊕⊕⊝⊝ | RR 1.54 | Study population | |
| 15 per 1,000 | 8 more per 1,000 | ||||
| Minor non‐GI bleeding | 1495 | ⊕⊕⊕⊝ | RR 2.37 | Study population | |
| 31 per 1,000 | 42 more per 1,000 | ||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by one level due to serious risk of bias. Allocation concealment was not reported in one study, lack of blinding of patients and personnel in all studies, and high risk of bias related to incomplete outcome data. 2 Downgraded by one level due to serious imprecision. Confidence interval suggests both potential benefit and potential harm. 3 Downgraded by one level due to serious imprecision. Confidence interval suggests both potential benefit and potential no effect. 4 Downgraded by one level due to serious imprecision. Confidence interval suggests both potential harm and potential no effect. 5 Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential harm and potential no effect. Low number of events. 6 Downgraded by two levels due to very serious imprecision. Confidence interval suggests both potential harm and potential benefit. Low number of events. 7 Some concern with risk of bias. Lack of blinding of patients and personnel in both studies. 8 Downgraded by one level due to serious inconsistency (unexplained heterogeneity I2=64%) and due to some concern with risk of bias. 9 Downgraded by two levels due to very serious inconsistency (unexplained heterogeneity I2=74%.) and due to some concern with risk of bias. 10 Downgraded by one level due to serious imprecision. Low number of events. | |||||
| Idraparinux secondary prophylaxis compared to VKA secondary prophylaxis in people with cancer with VTE | |||||
| Population: people with cancer with VTE receiving secondary prophylaxis Setting: outpatient Intervention: idraparinux prophylaxis Control: VKA prophylaxis | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with VKA secondary prophylaxis | Risk difference with idraparinux secondary prophylaxis | ||||
| All‐cause mortality | 284 | ⊕⊕⊕⊝ | RR 1.11 | Study population | |
| 283 per 1000 | 31 more per 1000 | ||||
| Recurrent VTE | 270 | ⊕⊕⊝⊝ | RR 0.46 | Study population | |
| 77 per 1000 | 42 fewer per 1000 | ||||
| Major bleeding | 270 | ⊕⊕⊝⊝ | RR 1.11 | Study population | |
| 38 per 1000 | 4 more per 1000 | ||||
| Minor bleeding – not reported | — | — | — | — | — |
| Health‐related quality of life – not reported | — | — | — | — | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; VKA: vitamin K antagonist; VTE: venous thromboembolism. | |||||
| GRADE Working Group grades of evidence | |||||
| aDowngraded one level due to serious imprecision, 95% CI was consistent with the possibility for important benefit (62 per 1000 absolute reduction) and possibility of important harm (167 per 1000 absolute increase), included 85 events. bDowngraded two level due to very serious imprecision, 95% CI was consistent with the possibility of important benefit (65 fewer per 1000) and possibility of important harm (25 more per 1000); included 15 events. cDowngraded two levels due to very serious imprecision, 95% CI was consistent with the possibility for important benefit (25 per 1000 absolute reduction) and possibility of important harm (98 per 1000 absolute increase), included 11 events. | |||||
| Term | Definition |
|---|---|
| Adjuvant therapy | A therapy given in addition to the primary treatment to decrease the risk of the cancer recurrence or to assist in the cure. |
| Anticoagulation | The process of hindering the clotting of blood especially by treatment with an anticoagulant. |
| Antithrombotic | Used against or tending to prevent thrombosis (clotting) |
| Coagulation | Clotting |
| Direct oral anticoagulants (DOAC) | Also known as NOACs are anticoagulant medications that require less monitoring compared to the traditional anticoagulants. |
| Deep vein thrombosis (DVT) | A condition marked by the formation of a thrombus within a deep vein (as of the leg or pelvis) that may be asymptomatic or be accompanied by symptoms (as swelling and pain) and that is potentially life‐threatening if dislodgment of the thrombus results in pulmonary embolism. |
| Fondaparinux | An anticoagulant medication |
| Hemostatic system | The system that shortens the clotting time of blood and stops bleeding. |
| Heparin | An enzyme occurring especially in the liver and lungs that prolongs the clotting time of blood by preventing the formation of fibrin. 2 forms of heparin that are used as anticoagulant medications are: unfractionated heparin (UFH) and low molecular weight heparins (LMWH). |
| Impedance plethysmography | A technique that measures the change in blood volume (venous blood volume as well as the pulsation of the arteries) for a specific body segment |
| Kappa statistic | A measure of degree of nonrandom agreement between observers, measurements of a specific categorical variable, or both. |
| Metastasis | The spread of a cancer cells from the initial or primary site of disease to another part of the body. |
| Parenteral nutrition | The practice of feeding a person intravenously, circumventing the gastrointestinal tract. |
| Pulmonary embolism (PE) | Embolism of a pulmonary artery or one of its branches that is produced by foreign matter and most often a blood clot originating in a vein of the leg or pelvis and that is marked by labored breathing, chest pain, fainting, rapid heart rate, cyanosis, shock and sometimes death. |
| Thrombocytopenia | Persistent decrease in the number of blood platelets that is often associated with hemorrhagic conditions. |
| Thrombosis | The formation or presence of a blood clot within a blood vessel. |
| Vitamin K antagonists | Anticoagulant medications. Warfarin is a vitamin K antagonist. |
| Warfarin | An anticoagulant medication that is a vitamin K antagonist that is used for anticoagulation. |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 All‐cause mortality (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.99 [0.88, 1.12] |
| 1.2 All‐cause mortality (time‐to‐event) Show forest plot | 2 | 810 | HR (IV, Random, 95% CI) | 0.94 [0.74, 1.20] |
| 1.3 Recurrent venous thromboembolism (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.59 [0.44, 0.80] |
| 1.4 Recurrent venous thromboembolism (time‐to‐event) Show forest plot | 2 | 810 | HR (IV, Random, 95% CI) | 0.49 [0.31, 0.78] |
| 1.5 Major bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 1.09 [0.55, 2.12] |
| 1.6 Minor bleeding (up to 6 months) (main analysis ‐ active cancer) Show forest plot | 4 | 1712 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.47, 1.27] |
| 1.7 Thrombocytopenia (up to 6 months) (main analysis‐ active cancer) Show forest plot | 1 | 138 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.52, 1.69] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 All‐cause mortality (6‐12 months) Show forest plot | 4 | 1060 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.72, 1.23] |
| 2.2 Recurrent venous thromboembolism (6‐12 months) Show forest plot | 4 | 1050 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.34, 1.15] |
| 2.3 Major bleeding (6‐12 months) Show forest plot | 4 | 1055 | Risk Ratio (M‐H, Random, 95% CI) | 0.77 [0.39, 1.53] |
| 2.4 Minor bleeding (6‐12 months) Show forest plot | 4 | 1055 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.57, 1.23] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 All‐cause mortality (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 0.97 [0.83, 1.14] |
| 3.2 Recurrent VTE (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.45, 0.88] |
| 3.3 Major bleeding (6 months) Show forest plot | 5 | 2994 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.83, 1.73] |
| 3.3.1 GI tract cancer | 4 | 854 | Risk Ratio (M‐H, Random, 95% CI) | 1.47 [0.76, 2.84] |
| 3.3.2 Non‐GI tract cancer | 4 | 1853 | Risk Ratio (M‐H, Random, 95% CI) | 1.05 [0.63, 1.73] |
| 3.3.3 GI tract cancer not specified | 1 | 287 | Risk Ratio (M‐H, Random, 95% CI) | 0.20 [0.01, 4.04] |
| 3.4 Major GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.62, 2.17] |
| 3.5 Major upper GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.18 [0.51, 2.76] |
| 3.6 Major lower GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 1.10 [0.43, 2.80] |
| 3.7 Major non‐GI bleeding (6 months) Show forest plot | 4 | 1838 | Risk Ratio (M‐H, Random, 95% CI) | 0.84 [0.42, 1.68] |
| 3.8 Minor bleeding (6 months) Show forest plot | 5 | 2854 | Risk Ratio (M‐H, Random, 95% CI) | 1.58 [1.15, 2.16] |
| 3.9 Minor GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.37 [0.41, 4.64] |
| 3.10 Minor upper GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.03 [0.04, 25.97] |
| 3.11 Minor lower GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 1.54 [0.72, 3.27] |
| 3.12 Minor non‐GI bleeding (6 months) Show forest plot | 2 | 1495 | Risk Ratio (M‐H, Random, 95% CI) | 2.37 [1.44, 3.89] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 All‐cause mortality (up to 6 months) Show forest plot | 1 | 284 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.78, 1.59] |
| 4.2 Recurrent VTE (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 0.46 [0.16, 1.32] |
| 4.3 Major bleeding (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.35, 3.56] |
| 4.4 Minor bleeding (up to 6 months) Show forest plot | 1 | 270 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.30, 1.60] |
