Quality and Quantity of Sleep and Factors Associated With Sleep Disturbance in Hospitalized Patients.

Importance: Although inadequate sleep has a proven negative association with health care outcomes, to date, no large-scale studies have examined sleep in general hospital wards. Objectives: To assess the subjective quantity and quality of sleep and to identify the hospital-related factors associated with sleep disturbances in hospitalized patients. Design: For this nationwide, single-day, multicenter, cross-sectional, observational study, which took place on February 22, 2017, all hospitals in the Netherlands were encouraged by word of mouth and conventional and social media to participate in this study. A total of 39 hospitals participated. Included patients were at least 18 years of age, were able to give informed consent, and had spent at least 1 night in a regular-care hospital ward. Exposures: Hospitalization in a regular-care ward. Main Outcomes and Measures: Quantity and quality of last night's sleep in the hospital compared with habitual sleep at home the month before hospitalization. The Consensus Sleep Diary and the Dutch-Flemish Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance item bank were used. Complementary questions assessed sleep-disturbing factors. Results: A total of 2005 patients were included (median age, 68 years; interquartile range, 57-77 years; 994 of 1935 [51.4%] were male [70 patients did not identify their sex]). Compared with habitual sleep at home, the total sleep time in the hospital was 83 minutes (95% CI, 75-92 minutes; P < .001) shorter. The mean number of nocturnal awakenings was 2.0 (95% CI, 1.9-2.1) times at home vs 3.3 (95% CI, 3.2-3.5) times during hospitalization (P < .001). Patients woke up 44 minutes (95% CI, 44-45 minutes; P < .001) earlier than their habitual wake-up time at home. A total of 1344 patients (70.4%) reported having been awakened by external causes, which in 718 (35.8%) concerned hospital staff. All aspects of sleep quality measured using PROMIS questions were rated worse during hospitalization than at home. The most reported sleep-disturbing factors were noise of other patients, medical devices, pain, and toilet visits. Conclusions and Relevance: This study demonstrated that the duration and quality of sleep in hospitalized patients were significantly affected and revealed many potentially modifiable hospital-related factors negatively associated with sleep. Raising awareness about the importance of adequate sleep in the vulnerable hospital population and introducing interventions to target sleep-disturbing factors may improve healing.

Parenteral anticoagulation in ambulatory patients with cancer.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: A comprehensive search included (1) an electronic search (February 2013) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1), MEDLINE (1966 to February 2013; accessed via OVID) and EMBASE(1980 to February 2013; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted data in duplicate on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), arterial thrombosis (e.g. stroke, myocardial infarction), major bleeding, minor bleeding and quality of life. MAIN RESULTS: Of 9559 identified citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 7622 participants for whom follow-up data were available. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin may have a small effect on mortality at 12 months and 24 months (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.92 to 1.01 and RR 0.95; 95% CI 0.90 to 1.00, respectively). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.56; 95% CI 0.42 to 0.74) and a clinically important increase in the risk of minor bleeding (RR 1.32; 95% 1.02 to 1.71). Results failed to show or to exclude a beneficial or detrimental effect of heparin on major bleeding (RR 1.14; 95% CI 0.70 to 1.85) or quality of life. Our confidence in the effect estimates (i.e. quality of evidence) was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for quality of life. AUTHORS' CONCLUSIONS: Heparin may have a small effect on mortality at 12 months and 24 months. It is associated with a reduction in venous thromboembolism and a likely increase in minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides, and should integrate the patient's values and preferences.

Cancer and venous thrombosis: current comprehensions and future perspectives.

Venous thromboembolism (VTE) is a common complication in all types of cancer and adversely impacts cancer prognosis. Randomized controlled trials with primary thromboprophylaxis in cancer patients generally show effective VTE relative risk reductions of up to 60%. However, absolute risks of VTE were fairly low. Thromboprophylaxis should therefore only be recommended to cancer patients at highest risk of VTE, who may benefit most from prophylaxis. Predictive risk models to identify patients at a high risk of VTE are promising, however additional validation is required. An increasing proportion of cancer-associated VTE is formed by incidental VTE, with similar risk factors and clinical consequences. Randomized trials are not yet available, but it seems reasonable to treat incidental VTE similarly to symptomatic VTE. In a substantial proportion of patients with unprovoked VTE without known cancer at the time of VTE diagnosis, concomitant or occult cancer is identified. Studies have investigated the value of extensive screening over routine examinations alone for occult cancer. Although extensive screening may be able to identify more occult cancers, its clinical benefit over routine screening has not been demonstrated.

Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). MAIN RESULTS: Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. AUTHORS' CONCLUSIONS: Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer.

PURPOSE: Earlier studies showed that low molecular weight heparin significantly prolongs the survival of a wide variety of patients with cancer without venous thromboembolism. This study was designed to confirm these findings in a more homogeneous group of patients with cancer. PATIENTS AND METHODS: In this multicenter, randomized, open-label study, patients with non-small-cell lung cancer (stage IIIB), hormone-refractory prostate cancer, or locally advanced pancreatic cancer were randomly assigned to nadroparin or to no nadroparin in addition to their standard anticancer treatment. In the nadroparin arm, subcutaneous nadroparin was administered for 6 weeks (2 weeks at therapeutic dose, and 4 weeks at half therapeutic dose). The patients were eligible to receive additional cycles of nadroparin (2 weeks at therapeutic dose, and 4 weeks of washout period). Outcomes were overall survival, time to progression, and major bleeding. All study outcomes were adjudicated by an independent, blinded committee. RESULTS: A total of 244 patients were allocated to nadroparin, and 259 were allocated to the control group. A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no-treatment arm (hazard ratio, 0.94; 95% CI, 0.75 to 1.18, adjusted for cancer type). No difference in time to progression was observed. The number of major bleedings was comparable at 4.1% in the nadroparin set and 3.5% in the control set. CONCLUSION: This study did not show a survival benefit of nadroparin in patients with advanced prostate, lung, or pancreatic cancer. Given the ongoing studies in this area and the previous data, the role of low molecular weight heparins in cancer survival remains undefined.

Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). MAIN RESULTS: Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. AUTHORS' CONCLUSIONS: Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences.

Heparin and survival in cancer patients.

The bi-directional association between cancer and the coagulation system has been known for almost 2 centuries. During the past 2 decades research has focused on the precise mechanisms through which cancer cells are able to induce a hypercoagulable state and how this leads to an environment favorable for cancer growth. Furthermore, the potential inhibitory effect of anticoagulant drugs on cancer progression has been explored. This article discusses these two aspects of the association.

Idraparinux versus standard therapy in the treatment of deep venous thrombosis in cancer patients: a subgroup analysis of the Van Gogh DVT trial.

Standard treatment with heparin followed by vitamin K antagonists is frequently complicated by bleeding and recurrent venous thromboembolism (VTE) in cancer patients with VTE. To compare the efficacy, safety and overall survival of long-term idraparinux treatment to standard therapy in cancer patients we conducted a post-hoc analysis in the subgroup of non-active and active cancer patients included in the Van Gogh DVT clinical trial. The cancer patients with deep venous thrombosis (DVT) and without pulmonary embolism (PE) were randomised to standard treatment or a once-weekly subcutaneous injection of idraparinux (2.5 mg), a synthetic pentasaccharide. 421 cancer patients were included. A total of 220 patients received idraparinux and 201 were allocated to standard therapy for three months (8%) or six months (92%). A recurrent VTE was observed during the first six months in 2.5% (n=5) of the idraparinux recipients compared to 6.4% (n=12) in the standard therapy group (hazard ratio 0.39, 95% confidence interval [CI]; 0.14-1.11). The rate of bleeding was comparable (odds ratio 0.89, 95% CI; 0.50-1.59). The outcomes were similar at three months after randomisation in all patients. Of the idraparinux recipients, 22.7% (n=50) died during the study period compared to 48 patients (23.9%) in the standard treatment group (hazard ratio 0.99, 95% CI; 0.66-1.48). In conclusion, no significant safety or survival differences were observed between cancer patients with DVT treated with idraparinux for six months compared to standard therapy. Fewer recurrent VTEs were observed in the idraparinux group; however, this was not statistically significant and also because of study limitations this should be interpreted with caution.

Idiopathic superficial thrombophlebitis and the incidence of cancer in primary care patients.

PURPOSE: The association of spontaneous venous thromboembolism with occult malignancy is well established. Less clear is the incidence of subsequent cancer in patients with superficial thrombophlebitis. We wanted to determine the incidence of cancer after an episode of spontaneous superficial thrombophlebitis in a large general practice population. METHODS: The objective of this study was to assess the incidence of newly diagnosed malignancies in patients within 2 years after the diagnosis of a spontaneous episode of superficial thrombophlebitis and to compare this incidence with nonexposed matched control patients and the Dutch population. The patients and their controls were identified by a search in the electronic patient records of 5 primary health care centers in Amsterdam, the Netherlands. A standardized morbidity ratio was calculated using data of the Dutch cancer registry. RESULTS: A total number of 277 patients with superficial thrombophlebitis were identified, of which 250 patients had no cancer at study entry. In 5 of these 250 patients (2%; 95% confidence interval [CI], 1%-5%), a new malignancy was diagnosed within 2 years after their superficial thrombophlebitis compared with 2% (95% CI, 1%-4%) in the control group. The standardized morbidity ratio was 1.1 (95% CI, 0.5-2.7). A recurrent episode of superficial thrombophlebitis was observed in 18 of the 250 patients, and in 1 patient cancer was diagnosed within 24 months after the first episode of superficial thrombophlebitis. CONCLUSION: We conclude that a single episode of unprovoked superficial thrombophlebitis diagnosed by a family physician is not associated with an increased risk of subsequent cancer.

Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease.

BACKGROUND: Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease. DESIGN AND METHODS: In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease. RESULTS: The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=-0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023). CONCLUSIONS: We conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles.

Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials.

In the initial treatment of venous thromboembolism (VTE) fondaparinux, a pentasaccharide, is a good alternative to heparin. Whether this is also true for cancer patients is unknown. We performed two post-hoc analyses of two randomized studies to compare efficacy, safety and overall survival of fondaparinux to standard initial (low-molecular-weight) heparin (LMWH) treatment in cancer patients with venous thromboembolism. Two hundred thirty-seven cancer patients with deep venous thrombosis (DVT) were initially treated with fondaparinux or enoxaparin. Two hundred forty cancer patients with pulmonary embolism (PE) received fondaparinux or unfractionated heparin. The initial treatment was followed by vitamin K antagonists. In DVT patients, the three-month recurrence rate was 5.4% in the enoxaparin recipients compared to 12.7% in those treated with fondaparinux [absolute difference 7.3%, 95% CI 0.1, 14.5]. A recurrence was observed in 8.9% of the PE patients treated with fondaparinux compared to 17.2% in the unfractionated heparin recipients [absolute difference -8.3, 95% CI -16.7, 0.1]. In both studies no difference in bleeding and overall survival was observed. Regarding overall survival and bleeding fondaparinux is comparable to enoxaparin and unfractionated heparin in cancer patients. No significant differences in recurrent VTE were observed when comparing fondaparinux with unfractionated or LMWH. Because of study limitations these results should be considered hypothesis-generating.

Parenteral anticoagulation may prolong the survival of patients with limited small cell lung cancer: a Cochrane systematic review.

BACKGROUND: To determine the efficacy and safety of heparin (unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)) and fondaparinux in improving the survival of patients with cancer. METHODS: We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We used a standardized form to extract in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, thromboembolic events, and bleeding events. We assessed the methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology RESULTS: Of 3986 identified citations, we included 5 RCTs, none of which evaluated fondaparinux. The quality of evidence was moderate for survival, low for major and minor bleeding, and very low for DVT. Heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95%CI = 0.65-0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95%CI = 0.38-0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95%CI = 0.60-1.06) or patients with advanced cancer (HR = 0.84; 95%CI = 0.68-1.03). The increased risk of bleeding with heparin was not statistically significant (relative risk (RR) = 1.78; 95%CI = 0.73-4.38). CONCLUSION: This review suggests a survival benefit of heparin in cancer patients in general, and in patients with limited small cell lung cancer in particular.

Biochemical markers predictive for bone marrow involvement in systemic mastocytosis.

Systemic mastocytosis is characterized by bone marrow involvement, which requires a bone marrow biopsy for diagnostic work-up. We questioned whether bone marrow involvement could be predicted using biochemical markers. We selected patients with various symptoms suggestive of indolent systemic mastocytosis, of whom 63 ultimately had bone marrow involvement. Patients suspected of aggressive mastocytosis, or mastocytosis associated with other hematologic diseases were excluded. Evaluation of 115 patients and 15 patient controls demonstrated a test accuracy for serum tryptase, urinary N(-) methylhistamine and N(-) methylimidazole acetic acid of 96%, 88% and 95% respectively. These markers provide an excellent pre-test probability of indolent systemic mastocytosis.