Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer.

BACKGROUND: Cancer increases the risk of thromboembolic events in patients including those receiving anticoagulation treatments. OBJECTIVES: To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer. SEARCH METHODS: We conducted a comprehensive search for studies of anticoagulation in cancer patients including 1. a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL Issue 12, 2012), MEDLINE, and EMBASE; 2. a handsearch of conference proceedings; 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. a search of clinicaltrials.gov for ongoing studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form, we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach. MAIN RESULTS: Of 9559 identified citations, 10 RCTs (11 reports) were eligible and reported data for 1981 patients with cancer. We excluded 14 studies in which patients with cancer constituted study subgroups, but did not report outcome data for them. Meta-analysis of seven RCTs comparing LMWH with VKA found no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). The remaining findings did not exclude a beneficial or harmful effect of LMWH compared with VKA for the outcomes of major bleeding (RR 1.07; 95% CI 0.52 to 2.19), minor bleeding (RR 0.89; 95% CI 0.51 to 1.55), or thrombocytopenia (RR 0.98; 95% CI 0.57 to 1.66). We judged the quality of evidence as low for mortality, major bleeding, and minor bleeding, and as moderate for recurrent VTE.One RCT comparing dabigatran with VKA did not exclude beneficial or harmful effects of one agent over the other. One RCT comparing six months' extension of anticoagulation with 18 months of ximelagatran 24 mg twice daily versus no extended ximelagatran did not exclude beneficial or harmful effects for the outcomes of reduction in VTE, mortality, and minor bleeding. One RCT comparing once-weekly subcutaneous injection of idraparinux for three or six months versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) suggested a reduction in recurrent VTE (HR 0.39; 95% CI 0.14 to 1.11) at six months, but did not exclude beneficial or harmful effects for the outcomes of mortality (HR 0.99; 95% CI 0.66 to 1.48) and major bleeding (RR 1.04; 95% CI 0.39 to 2.83). AUTHORS' CONCLUSIONS: For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and harms and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer.

BACKGROUND: The choice of the appropriate perioperative thromboprophylaxis in patients with cancer depends on the relative benefits and harms of low molecular weight heparin (LMWH) and unfractionated heparin (UFH). OBJECTIVES: To update a systematic review of the evidence for the relative efficacy and safety of LMWH and UFH for perioperative thromboprophylaxis in patients with cancer. SEARCH METHODS: We performed a comprehensive search for trials of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. We also handsearched conference proceedings, reviewed reference list of included studies, used the 'related citations' feature in PubMed, and searched clinicaltrials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) that enrolled patients with cancer undergoing a surgical intervention and compared the effects of LMWH to UFH on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, or thrombocytopenia. DATA COLLECTION AND ANALYSIS: Two review authors independently used a standardized form to extract in duplicate data on participants, interventions, outcomes of interest, and risk of bias. Where possible, we conducted meta-analyses using the random-effects model. MAIN RESULTS: Of 9559 identified unique citations, we included 16 RCTs with 12,890 patients with cancer, all using preoperative prophylactic anticoagulation. We identified no new study with this update. The overall quality of evidence was moderate. The meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.74 to 1.08), PE (RR 0.73; 95% CI 0.34 to 1.54), symptomatic DVT (RR 0.50; 95% CI 0.20 to 1.28), asymptomatic DVT (RR 0.81; 95% CI 0.66 to 1.01),major bleeding (RR 0.85; 95% CI 0.52 to 1.37), and minor bleeding (RR 0.92; 95% CI 0.47 to 1.79). LMWH was associated with lower incidence of wound hematoma (RR 0.68; 95% CI 0.52 to 0.88) but higher volume of intraoperative transfusion (mean difference (MD) 74 mL; 95% CI 47 to 102). The meta-analyses found no statistically significant differences for any of the following outcomes: reoperation for bleeding (RR 0.72; 95% CI 0.06 to 8.48) , intraoperative blood loss (MD= -6mL; 95% CI -87 to 74), postoperative transfusion (MD= 79mL; 95% CI -54 to 211), postoperative drain volume (MD= 27mL; 95% CI -44 to 98), and thrombocytopenia (RR 1.33; 95% CI 0.59 to 3.00). AUTHORS' CONCLUSIONS: We found no difference between perioperative thromboprophylaxis with LMWH versus UFH in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in patients with cancer. Further trials are needed to evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population more thoroughly.

Positive airway pressure therapy in patients with opioid-related central sleep apnea.

PURPOSE: This study aims to compare treatment response and adherence rate to positive airway pressure (PAP) in patients with opioid-related central sleep apnea (O-CSA) and idiopathic central sleep apnea (I-CSA). METHODS: We performed a retrospective chart over a 5-year period performed at a VA sleep center. Continuous PAP (CPAP) was prescribed initially for all participants. For those nonresponders (apnea hypopnea index (AHI) of >10/h), bi-level PAP (BiPAP) or adaptive servoventilation (ASV) was instituted upon provider's discretion. Adherence to therapy was checked with the built-in meter. RESULTS: Thirty-four patients with O-CSA and 61 with I-CSA were included in the analysis. The two groups were comparable with respect to age, body mass index (BMI), Epworth Sleepiness Scale, and burden of comorbidities. The mean daily equivalent dose of morphine in the O-CSA was 168 mg (range 30-1,217 mg). In the O-CSA group, 24% of PAP-naïve patients responded to CPAP compared to 38% in the I-CSA group. BiPAP and ASV were comparable in eliminating central events in both O-CSA (66 versus 60 %) and I-CSA (93 versus 90%), respectively. Eight patients (24%) with O-CSA and six patients (10%) with I-CSA were considered nonresponders. The adherence rate was 48 and 24% in the I-CSA group compared to 23 and 18% in the O-CSA group at 3 and 12 months following initiation of effective treatment (p = 0.04 and p = 0.6). CONCLUSIONS: The presence of O-CSA does not preclude an adequate response to CPAP. Adherence rate to PAP was poor in both the O-CSA and I-CSA groups. Further studies are needed to define optimal adherence rate and long-term benefits of PAP in CSA.

Systematic evaluation of the methodology of randomized controlled trials of anticoagulation in patients with cancer.

BACKGROUND: Randomized controlled trials (RCTs) that are inappropriately designed or executed may provide biased findings and mislead clinical practice. In view of recent interest in the treatment and prevention of thrombotic complications in cancer patients we evaluated the characteristics, risk of bias and their time trends in RCTs of anticoagulation in patients with cancer. METHODS: We conducted a comprehensive search, including a search of four electronic databases (MEDLINE, EMBASE, ISI the Web of Science, and CENTRAL) up to February 2010. We included RCTs in which the intervention and/or comparison consisted of: vitamin K antagonists, unfractionated heparin (UFH), low molecular weight heparin (LMWH), direct thrombin inhibitors or fondaparinux. We performed descriptive analyses and assessed the association between the variables of interest and the year of publication. RESULTS: We included 67 RCTs with 24,071 participants. In twenty one trials (31%) DVT diagnosis was triggered by clinical suspicion; the remaining trials either screened for DVT or were unclear about their approach. 41 (61%), 22 (33%), and 11 (16%) trials respectively reported on major bleeding, minor bleeding, and thrombocytopenia. The percentages of trials satisfying risk of bias criteria were: adequate sequence generation (85%), adequate allocation concealment (61%), participants' blinding (39%), data collectors' blinding (44%), providers' blinding (41%), outcome assessors' blinding (75%), data analysts' blinding (15%), intention to treat analysis (57%), no selective outcome reporting (12%), no stopping early for benefit (97%). The mean follow-up rate was 96%. Adequate allocation concealment and the reporting of intention to treat analysis were the only two quality criteria that improved over time. CONCLUSIONS: Many RCTs of anticoagulation in patients with cancer appear to use insufficiently rigorous outcome assessment methods and to have deficiencies in key methodological features. It is not clear whether this reflects a problem in the design, conduct or the reporting of these trials, or both. Future trials should avoid the shortcomings described in this article.

Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer.

BACKGROUND: Cancer increases the risk of thromboembolic events even while on anticoagulation. OBJECTIVES: To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively-confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach. MAIN RESULTS: Of 8187 identified citations, nine RCTs were eligible and reported data for 1908 patients with cancer. Meta-analysis of seven RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). Other results did not exclude a beneficial or harmful effect of LMWH compared to VKA for the outcomes of major bleeding (RR 1.05; 95% CI 0.53 to 2.10) or thrombocytopenia (RR 1.02; 95% CI 0.60 to 1.74). The quality of evidence was low for mortality, major bleeding and minor bleeding and moderate for recurrent VTE. One RCT comparing six months extension of anticoagulation with 18 months ximelagatran 24 mg twice daily versus placebo found a reduction in VTE (HR 0.16; 95% CI 0.09 to 0.30) but did not exclude beneficial or harmful effects for the outcomes of mortality and bleeding. One RCT, comparing dabigatran to VKA, did not exclude beneficial or harmful effect of one agent over the other. AUTHORS' CONCLUSIONS: For the long-term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies.

Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer.

BACKGROUND: The choice of the appropriate perioperative thromboprophylaxis in patients with cancer depends on the relative benefits and harms of low molecular weight heparin (LMWH) and unfractionated heparin (UFH). OBJECTIVES: To systematically review the evidence for the relative efficacy and safety of LMWH and UFH for perioperative thromboprophylaxis in patients with cancer. SEARCH METHODS: A comprehensive search for trials of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. SELECTION CRITERIA: Randomized controlled trials (RCTs) that enrolled cancer patients undergoing a surgical intervention and compared the effects of LMWH to UFH on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, and thrombocytopenia. DATA COLLECTION AND ANALYSIS: Two review authors used a standardized form to independently extract in duplicate data on risk of bias, participants, interventions and outcomes of interest. Where possible, we conducted meta-analyses using the random-effects model. MAIN RESULTS: Of 8187 identified citations, we included 16 RCTs with 11,847 patients in the meta-analyses, all using preoperative prophylactic anticoagulation. The overall quality of evidence was moderate. The meta-analysis did not conclusively rule out either a beneficial or harmful effect of LMWH compared to UFH for the following outcomes: mortality (RR = 0.90; 95% CI 0.73 to 1.10), symptomatic DVT (RR = 0.73; 95% CI 0.23 to 2.28), PE (RR = 0.59; 95% CI 0.25 to1.41), minor bleeding (RR = 0.88; 95% CI 0.47 to 1.66) and major bleeding (RR = 0.84; 95% CI 0.52 to 1.36). LMWH was associated with lower incidence of wound hematoma (RR = 0.60; 95% CI 0.43, 0.84) while UFH was associated with higher incidence of intra-operative transfusion (RR = 1.16; 95% CI 0.69,1.62). AUTHORS' CONCLUSIONS: We found no difference between perioperative thromboprophylaxis with LMWH verus UFH in their effects on mortality and embolic outcomes in patients with cancer. Further trials are needed to more carefully evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population.