Efficacy and Safety of Anticoagulant Therapy for the Treatment of Acute Cancer-Associated Thrombosis: A Systematic Review and Meta-Analysis

Background

Current clinical practice guidelines all recommend the use of therapeutic doses of low molecular weight heparins (LMWH) for the initial and long-term treatment of cancer-related thrombosis. The use of vitamin-K antagonists (VKA) is acceptable if LMWH is not available. Direct oral anticoagulants (DOACs) have been shown to be comparable to conventional therapy for the acute treatment of VTE but their efficacy and safety in cancer patients remains uncertain.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the EBM reviews. Randomized controlled trials (RCTs) reporting rates of recurrent VTE and major bleeding in cancer patients were included. Relative risks (RR) (95% confidence intervals (CI)) for these outcomes were generated.

Results

A total of 9 RCTs (2310 patients) were included in our analysis. In comparison to VKA, LMWH showed a significant reduction in recurrent VTE events (RR: 0.52; 95% CI: 0.36 to 0.74) whereas DOACs did not (RR: 0.66; 95% CI: 0.39 to 1.11). LMWH was associated with a non significant increase in the risk of major bleeding (RR: 1.06; 95% CI: 0.5 to 2.23) whereas DOACs showed a non significant reduction (RR: 0.78; 95% CI: 0.42 to 1.44). Annualized risks of recurrent VTE and major bleeding among patients randomized to VKA were higher in the LMWH studies as compared to the studies assessing DOACs suggesting that a higher risk cancer population were enrolled in the LMWH studies.

Conclusions

LMWH should be used for the treatment of acute cancer-associated thrombosis. The use DOACs cannot be supported until trials comparing them to LMWH are conducted.     

Direct oral anticoagulants in the treatment of acute venous thromboembolism: A systematic review and meta-analysis

Introduction

Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality.

Materials and methods

We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software).

Results

Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, − 0.6%; 95% confidence interval − 1.0% to − 0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis.

Conclusions

The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.     

Efficacy of low- molecular- weight- heparin versus vitamin K antagonists for long term treatment of cancer-associated venous thromboembolism in adults: a systematic review of randomized controlled trials

Background

Patients with malignancy have a 4-fold increase in the risk of developing a venous thrombosis and a 3-fold increase in risk of bleeding. Both low-molecular-weight-heparin (LMWH) and vitamin K antagonists (VKA) have been used for treatment of cancer-associated thrombosis. However, the best anticoagulation approach remains a matter of debate.

Objective

In adult patients with cancer and an acute venous thromboembolic event we sought to determine the rates of recurrent venous thromboembolism (VTE) and major hemorrhage when treated with prolonged LMWH therapy compared to vitamin-K antagonists.

Patients/Methods

A systematic literature search strategy was used to identify potential trials on MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and Medline in-process using an OVID interface. Risk assessment of bias of randomized controlled trials (RCTs) was performed according to the Cochrane Collaboration-Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome measure was symptomatic VTE recurrence rate during the anticoagulation period. Relative risk (RR) was used as the primary measurement with 95% confidence intervals (CIs). Pooled measurements were calculated using random –effects and fixed-effects model.

Results

Five articles met our inclusion criteria. All compared LMWH and VKA for secondary prevention of VTE. The pooled RR of VTE recurrence was 0.53 (95% CI: 0.36-0.76; p = 0.007). The pooled RR of major bleeding was 0.98 (95% CI: 0.49-1.93, p = 0.95). Minor bleeding events and all cause mortality were similar between the 2 intervention arms.

Conclusions

The results of our review suggest that the long term use of LMWH after the acute first week of treatment is superior to VKAs for secondary prevention of venous thromboembolism in adult patients with cancer.     

Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis

Introduction

Patients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis.

Material and Methods

A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3 months after the index recurrent event.

Results

Fifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes.

Conclusion

Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancer-associated thrombosis despite anticoagulant therapy.     

Treatment patterns of venous thromboembolism in a real-world population: The Q-VTE study cohort

Background

Few studies have assessed treatment patterns of acute venous thromboembolism (VTE) in a real-world population. We aimed to describe anticoagulant treatment patterns for acute VTE using healthcare databases of Québec, Canada.

Methods

We used linked healthcare databases of the province of Québec, Canada to identify all incident cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) between 2000 and 2009. We formed two patient cohorts, one with definite cases (definite VTE cohort, N = 40,776) and the other including cases with definite or probable VTE (any VTE cohort, N = 54,803) that were followed until death, end of health coverage, or end of study (December 31, 2009).

Results

In the definite cohort, 73.6% of subjects were dispensed an anticoagulant following the diagnosis of VTE. Of those who were dispensed a vitamin K antagonist (VKA), median duration of use was 61 days (interquartile range 89). VKA initiation was more likely in patients with pulmonary embolism than deep vein thrombosis alone (HR 1.62, 95% CI (1.58-1.66)). Among outpatients, those managed initially in the outpatient setting were less likely to initiate VKA therapy (HR 0.75, 95% CI (0.68-0.77)), while those requiring admission to hospital for VTE management were more likely to initiate (HR 1.81, 95% CI (1.76-1.87)). Findings were similar in the any VTE cohort.

Conclusion

Our study describes VTE treatment patterns in a real-world setting and suggests that there may be important gaps. These may include significant numbers of patients who did not initiate oral anticoagulant therapy, particularly in the outpatient setting, and shorter duration of oral anticoagulant use than recommended.     

Rivaroxaban for the treatment of venous thromboembolism. A “real-life” perspective in 103 patients

Introduction

Randomized clinical trials have demonstrated non-inferiority of rivaroxaban compared with vitamin K antagonists (VKAs) in the treatment of venous thromboembolism (VTE). Our objective was to analyze in real life, tolerance, recurrence, bleeding and adverse events of rivaroxaban in patients with acute symptomatic VTE.

Material and Methods

Open follow-up study of a cohort of patients aged 18 and over diagnosed with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) treated with rivaroxaban from December 2011 to January 2014.

Results

The total number of patients treated with rivaroxaban was 103. The mean age was 58 +/-17 years. The most frequent co-morbidities were: hypertension (30.0%), dyslipidemia (23.3%) and respiratory disease (25.2%). The type of thromboembolic event treated was: DVT (64.1%), PE (18.4%), DVT + PE (17.5%). Of the rivaroxaban-treated patients, 30% did so from the initial anticoagulant therapy and the other 70% in long-term or extended anticoagulant therapy. The median time of treatment with rivaroxaban was 5 months. There was one recurrence and no deaths occurred. Six patients had bleeding, one of which was severe.

Conclusions

Rivaroxaban provides a therapeutic alternative in a group of patients with VTE with advantages over VKAs, because of the convenience in dosing, lack of requirements for periodic monitoring and limited interaction with other drugs.     

Meta-Analysis to Assess the Quality of International Normalized Ratio Control and Associated Outcomes in Venous Thromboembolism Patients

Introduction

Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients.

Materials and Methods

We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed.

Results

Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient = -0.46, p = 0.01) and major bleeding (beta-coefficient = -0.30, p = 0.02). Patients with an INR < 2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR > 3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p = 0.04) and treated in the community (-7%, p < 0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p = 0.003) greater time.

Conclusions

Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.     

Further evidence in support of the association between venous thrombosis and atherosclerosis: A case–control study

Introduction

Whether there is an association between venous thromboembolism (VTE) and atherosclerosis is still controversial.

Aims

In a case–control study conducted on subjects older than 50, we assessed the prevalence of symptomatic or subclinical atherosclerosis in a group of unselected patients with unprovoked VTE, and compared it with that of patients with secondary VTE and of matched control individuals free from VTE disorders.

Methods

Cases and controls were enquired about the presence of previous symptomatic manifestations of atherosclerosis. Those with a negative history underwent the ultrasound assessment of carotid arteries following a standardized procedure. An intima-media thickness higher than 0.9 mm or the detection of at least one carotid plaque was regarded as a subclinical manifestation of atherosclerosis. After adjusting for age, gender and risk factors for atherosclerosis, we calculated the odds ratio (OR) for symptomatic or subclinical atherosclerosis in patients with unprovoked VTE as compared to those with secondary VTE and controls.

Results

We recruited 100 patients with unprovoked VTE, 100 with secondary VTE and 100 control individuals. In patients with unprovoked VTE, the adjusted OR for symptomatic or subclinical atherosclerosis was 5.1 (95% CI, 2.0 to 13.1) in comparison to patients with secondary VTE, and 14.5 (95% CI, 5.8 to 36.3) in comparison to controls. The prevalence of atherosclerosis was higher in patients with secondary VTE than in controls (OR, 3.1; 95% CI, 1.6 to 6.1).

Conclusion

The results of this study confirm the presence of a strong association between venous thrombosis and atherosclerosis.     

Thromboembolism,major bleeding and mortality in patients with mechanical heart valves- a population-based cohort study

Introduction

Low incidences of thromboembolism (TE) and bleeding in patients with mechanical heart valves (MHV) have previously been reported. This study assesses the incidence of and clinical risk factors predicting TE, major bleeding and mortality in a clinical setting.

Methods and results

All 546 patients undergoing anticoagulation treatment due to MHV replacement at hospitals in Malmö and Sundsvall in Sweden were monitored during 2008–2011 and the incidence of TE, major bleeding and mortality was prospectively followed. There were 398, 122 and 26 patients in the aortic group (AVR), mitral (MVR) group and the combined aortic/mitral valve group respectively. The incidence of TE was 1.8 and 2.2 per 100 patient-years in the AVR group MVR group respectively. The corresponding incidences of bleeding were 4.4 and 4.6, respectively. Independent predictor of thromboembolism was vascular disease (Odds ratio {OR}: 4.2; 95% CI: 1.0-17.4). Predictor of bleeding was previous bleeding (OR: 2.7; 95% CI: 1.4-5.3). Independent predictors of mortality was age (Hazard ratio {HR}: 1.03; 95% CI: 1.00-1.05), hypertension (HR: 2.4; 95% CI: 1.3-4.5), diabetes (HR: 2.4; 95% CI: 1.3-4.3) and alcohol overconsumption (HR: 5.2; 95% CI: 1.7-15.9). Standardized mortality/morbidity ratio for mortality and AMI was 0.99 (95% CI: 0.8-1.2) and 0.87 (95% CI: 0.5-1.2) respectively.

Conclusion

The incidence of TE and major bleeding in this unselected clinical population exceeds that of previously reported retrospective and randomized trials. Despite this, mortality is equal to that of the general population.     

Efficacy and safety of weight-adjusted heparin prophylaxis for the prevention of acute venous thromboembolism among obese patients undergoing bariatric surgery: A systematic review and meta-analysis

Background

The bariatric surgical population is a particularly high risk population for VTE. It is unclear if standard (i.e. non-adjusted) thromboprophylaxis doses of low-molecular weight or unfractionated heparin provide adequate protection for obese patients undergoing bariatric surgery, or if higher doses are required. We sought to determine whether a weight based thromboprophylactic dosing regimen is safe and effective in the post-operative period for obese patients undergoing bariatric surgery.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.

Results

A total of 6 studies (1 RCT, 4 cohort studies and one quasi experimental trial) containing 1,858 patients were include in the systematic review. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95% CI: 0.2 to 1.0%) compared to 2.0% (95% CI: 0.1 to 6.4%) for those that did not weight adjust doses. Rates of major bleeding were similar for both groups: 1.6% (95% CI: 0.6 to 3.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1% to 3.9%) for those receiving standard doses of heparin products.

Conclusions

Adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to be associated with a lower rate of in hospital VTE compared to a strategy of not adjusting the dose, although this did not reach statistical significance. This practice does not lead to an increase in adverse major bleeding events.     

Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis

Introduction

Bleeding complications occur more frequently in women than men in clinical trials of warfarin and thrombolytics. It is unknown whether these sex-related differences exist for new oral anticoagulants, including dabigatran, rivaroxaban, and apixaban. To determine whether women suffer more bleeding complications with these agents, we conducted a systematic review and meta-analysis of randomized controlled trials on new oral anticoagulants for venous thromboembolism (VTE).

Materials and Methods

Medline, Embase, and the Cochrane-controlled trial register on the Cochrane library were searched to identify studies that evaluated novel oral anticoagulants versus any comparator, and reported outcomes, including major bleeding and recurrent VTE, stratified by sex. No language restrictions were applied. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled relative risk was estimated using a random effects model.

Results

Eight studies were eligible, comprising 9417 patients. There was no difference in the primary efficacy outcome of recurrent VTE between men and women [Relative Risk (RR) 1.02, 95% confidence interval (CI) 0.74-1.39]. However, men had less major bleeding with novel oral anticoagulants compared to women [RR 0.79, 95% CI 0.66-0.97, p = 0.03]. All-cause mortality was not reported by sex in any of the studies.

Conclusion

Women suffer more bleeding complications than men when receiving novel oral anticoagulants for VTE. Future clinical trials should report outcomes stratified by sex, and further studies are needed to investigate the clinical impact of this sex-related safety difference.     

Cystatin C and creatinine as markers of bleeding complications,cardiovascular events and mortality during oral anticoagulant treatment

Introduction

Impaired kidney function has been linked to both ischemic events as well as bleeding complications in several clinical conditions. Our aim was to investigate if cystatin C, creatinine and calculated glomerular filtration rate (eGFR) were related to future risk of bleeding complications, cardiovascular events or all-cause mortality during oral anticoagulant treatment.

Materials and methods

In a cohort study, 719 patients on long-term vitamin K antagonist (VKA) treatment were followed for a mean of 4.2 years. Blood sampling was taken at inclusion and patients were followed prospectively. Cystatin C and creatinine were analysed and eGFR was calculated. All medical records were reviewed. Major bleeding events, myocardial infarctions, strokes, arterial emboli, and deaths were recorded and classified.

Results

After adjustment for age, no association between cystatin C, creatinine or eGFR and major bleeding was found. Cystatin C was independently associated with cardiovascular events (hazard ratio 1.50 (95% CI: 1.27-1.77)) and all-cause mortality (hazard ratio 1.62 (95% CI: 1.38-1.90)).Creatinine was only associated with all-cause mortality, while eGFR was not associated with any of the outcomes.

Conclusions

Our findings underscore the superiority of cystatin C as a marker of cardiovascular risk compared to creatinine or eGFR. VKA-treated patients with increased cystatin C levels should be considered to be at an increased risk of cardiovascular events, and not bleeding complications.     

Renal failure as a risk factor for venous thromboembolism in critically Ill patients: A cohort study

Rationale

The relationship between kidney function and venous thromboembolism (VTE) in critically ill patients is not well studied. The main objective of this study was to evaluate this relationship in patients admitted to a medical-surgical intensive care unit (ICU).

Methods

This was a retrospective study of 798 patients admitted to a tertiary-care ICU and prospectively followed for the development of clinically suspected and radiologically diagnosed deep venous thrombosis or pulmonary embolism. Patients were divided based on admission creatinine and dialysis history into five groups: normal kidney function, RIFLE classes R, I and F (combined = acute kidney injury [AKI]) and endstage renal disease (ESRD). We compared VTE prophylaxis practices and VTE incidence in these groups and evaluated renal failure as a VTE risk factor using multivariate Cox regression analysis.

Results

Of the 798 patients, 27.2% had AKI and 10.1% had ESRD. Unfractionated heparin use was similar in the five groups but enoxaparin use was less frequent in AKI (13.4%) and ESRD (3.8%) patients compared with patients with normal kidney function (39.0%). VTE occurred in 7.6% of patients with normal renal function, 7.8% AKI patients and 2.5% ESRD patients (p = 0.22). The adjusted hazard ratios for VTE compared to patients with normal kidney function were 0.35 (95% confidence interval [CI], 0.08-1.47) for RIFLE class R, 1.19 (95% CI, 0.83-1.70) for RIFLE class I, 0.82 (95% CI, 0.59-1.14) for RIFLE class F and 0.71 (95% CI, 0.49-1.02, p = 0.06) for ESRD.

Conclusions

Neither AKI nor ESRD was an independent risk factors for critically ill patients.     

Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism

Background

Numerous new oral anticoagulants (NOACs) have been compared to a parenteral anticoagulant/oral vitamin K antagonist (VKA) for the treatment of acute venous thromboembolism (VTE). We aimed to conduct a systematic review and adjusted indirect comparison meta-analysis to compare the efficacy and safety of NOACs for this indication.

Methods

We conducted a systematic literature search through November 2013 for randomized trials that evaluated treatment of acute VTE with a NOAC including rivaroxaban, apixaban, dabigatran and edoxaban. Trials had to report at least one of the following outcomes of interest: mortality, recurrent VTE, recurrent pulmonary embolism (PE), recurrent deep vein thrombosis (DVT), or major bleeding. Included trials were evaluated for quality using the Cochrane Risk of Bias tool. We performed an adjusted indirect comparison meta-analysis to evaluate the comparative efficacy and safety of NOACs, reporting relative risks (RRs) and 95% confidence intervals for each outcome.

Results

Six trials (n = 27,069) met inclusion criteria, one each evaluating apixaban and edoxaban and two trials each evaluating rivaroxaban and dabigatran. Risk of bias was low for all trials. NOACS did not differ significantly in the risk of mortality, recurrent VTE, recurrent PE or recurrent DVT. Dabigatran increased major bleeding risk compared to apixaban [RR 2.69 (1.19 to 6.07)] as did edoxaban compared to apixaban [RR 2.74 (1.40 to 5.39)].

Conclusion

Although NOACs do not appear to differ in the efficacy of treating acute VTE, data suggests apixaban to be the safer than some of its competitors.     

Incidence and risk factors of symptomatic venous thromboembolism related to implanted ports in cancer patients

Introduction

The true incidence of symptomatic implanted port related venous thromboembolism (VTE) in cancer patients is unclear and there is very limited data on its associated risk factors.

Materials and methods

We performed a retrospective cohort study of consecutive cancer outpatients who received an ultrasound guided implanted port insertion for the administration of chemotherapy. The primary outcome measure was symptomatic VTE. Univariable and multivariable logistic regression analyses were used to identify risk factors for symptomatic VTE.

Results

A total of 400 cancer patients with a newly inserted implanted port for deliverance of chemotherapy were included in the study. Median age was 58 years (range of 21 to 85 years) and 120 (30%) were males. Patients were followed for a median of 12 months and none received thrombophrophylaxis. Of the 400 patients included in the analysis, 34 patients (8.5%; 95% CI: 6.0 to 11.7%) had symptomatic VTE (16 DVTs, 16 PEs, and 2 with both). In the univariate analyses, metastatic disease, male gender and right sided implanted port insertion were significantly associated with the risk of VTE. In the multiple-variable analysis, male gender (OR 2.17, p = 0.04) and presence of metastases (OR 8.22, p < 0.01) were the two significant independent predictors of implanted port related VTE.

Conclusion

Symptomatic VTE is a frequent complication in cancer patients with implanted port receiving chemotherapy. Gender and presence of metastatic disease are independent risk factors for symptomatic VTE. Future trials assessing the role of thromboprophylaxis among these higher risk patients are needed.     

Erythropoiesis-stimulating agents and thrombotic events in dialysis patients

Background

Erythropoiesis-stimulating agents (ESA) have been associated with a higher cardiovascular event and mortality rate in dialysis patients. The ESA-associated risk of arterial thrombotic events is mainly based on composite endpoints of anemia-correction trials targeting high hemoglobin levels. The ESA-associated risk of venous thromboembolism (VTE) has not been studied in dialysis patients yet. We therefore aimed to determine the association between ESA use and dose with ischemic stroke, myocardial infarction (MI) and VTE.

Materials and Methods

In NECOSAD, a Dutch cohort study of incident dialysis patients, data on ESA use and dose, comorbidities and laboratory parameters were routinely collected every 6 months. Thrombotic events were collected by chart review of all dialysis patients from 6 participating centers. Time-dependent Cox regression analysis was performed to calculate hazard ratios (HR) with 95% confidence interval (CI) for ischemic stroke, MI and VTE with updated information on ESA use and dose.

Results

Patients with ESA had a 2 times lower ischemic stroke rate than patients without ESA: adjusted HR 0.45 (95% CI 0.23-0.90), and an adjusted HR of 1.12 (95% CI 0.58-2.14) for MI. No evident ESA dose response effect was present. Unadjusted HR for VTE was 0.41 (95% CI 0.11-1.50) for patients with ESA compared to patients without, but the low event rate made further adjustments impossible.

Conclusions

In our observational cohort of dialysis patients, reflecting everyday clinical practice, ESA was not associated with an excess of thrombotic events. Further investigation is needed to enlighten the true cause of ESA-associated cardiovascular events and mortality.     

Two years outcome of isolated distal deep vein thrombosis

Background

Isolated distal deep vein thrombosis (IDDVT) is frequently found in symptomatic outpatients, but its long term outcome is still uncertain.

Aims

To assess IDDVT long term outcome and the impact of IDDVT characteristics on outcome.

Methods

In a prospective, single center study we enrolled symptomatic outpatients in whom IDDVT was detected by whole-leg compression ultrasonography. Patients with provoked IDDVT were treated with low molecular weight heparins (LMWH) for 30 days while those with unprovoked IDDVT received with vitamin K antagonists (VKA) for three months. The primary end-point was the rate of the composite of pulmonary embolism (PE), proximal deep vein thrombosis (DVT), and IDDVT recurrence/extension during 24 month follow-up.

Results

90 patients (age 61 ± 18, male 48.9%) were enrolled. Risk factors for thrombosis were reduced mobility (34.4%), obesity (25.3%), surgery (15.6%), and previous DVT (15.6%) and cancer in 8 patients (8.9%). Eighty-eight patients were treated (56 with LMWH and 32 with VKA). During follow-up (median 24 ± 2 months), 17 events were recorded, which included 3 PE (two in cancer patients), 4 proximal DVTs (one in cancer patient) and 10 IDDVT. Male sex (HR 4.73 CI95%: 1.55-14.5; p = 0.006) and cancer (HR 5.47 CI95%: 1.76-17.6; p = 0.003) were associated with a higher risk of complications, whereas IDDVT anatomical characteristics, anticoagulant therapy type, and provoked IDDVT were not.

Conclusions

The risk of recurrent venous thromboembolism after IDDVT may be relevant in male patients or in patients with active cancer. Larger studies are needed to address this issue.     

Outpatient treatment of symptomatic pulmonary embolism: A systematic review and meta-analysis

Background

Patients with acute deep vein thrombus (DVT) can safely be treated as outpatients. However the role of outpatient treatment in patients diagnosed with a pulmonary embolism (PE) is controversial. We sought to determine the safety of outpatient management of patients with acute symptomatic PE.

Materials and Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.

Results

A total of 1258 patients were included in the systematic review. The rate of recurrent venous thromboembolism (VTE) in patients with PE managed as outpatients was 1.47% (95% CI: 0.47 to 3.0%; I²: 65.4%) during the 3 month follow-up period. The rate of fatal PE was 0.47% (95% CI: 0.16 to 1.0%; I²: 0%). The rates of major bleeding and fatal intracranial hemorrhage were 0.81% (95% CI: 0.37 to 1.42%; I²: 0%) and 0.29% (95% CI: 0.06 to 0.68%; I²: 0%), respectively. The overall 3 month mortality rate was 1.58% (95% CI: 0.71 to 2.80%; I²: 45%). The event rates were similar if employing risk stratification models versus using clinical gestalt to select appropriate patients for outpatient management.

Conclusions

Independent of the risk stratification methods used, the rate of adverse events associated with outpatient PE treatment seems low. Based on our systematic review and pooled meta-analysis, low-risk patients with acute PE can safely be treated as outpatients if home circumstances are adequate.     

Risk factors for recurrent venous thromboembolism in young and middle-aged women

Background

It is a matter of debate whether women with an episode of VTE associated with estrogen have a lower risk of recurrence than women with an unprovoked VTE.

Objectives

To identify risk factors for recurrent VTE in women and to assess the risk of recurrent VTE associated with combined oral contraceptives (CHC) or menopausal hormone treatment (HT), compared to surgery-related and unprovoked VTE.

Patients/Methods

A cohort of 974 women aged 18–64 years with a first episode of VTE were followed-up for a median time of 5.2 years. All women were previously included as cases in the Swedish nation-wide case–control study “Thrombo Embolism Hormone Study” (TEHS). Hazard ratios for recurrence were calculated using univariable and multivariable Cox proportional hazards model.

Results

A total of 102 patients (10%) suffered from recurrent VTE. The annual rate of recurrence was 1.0% in patients with surgery/cast, 2.0% in patients with CHC/HT and 3.2% in patients with unprovoked first VTE. Adjusted hazards ratio (HR_a) for recurrence was 0.35 (95% CI 0.20-0.61) in women with VT provoked by surgery/cast while women with estrogen-associated VTE had a HR_a of 0.70 (95% CI 0.43-1.20) compared to women with unprovoked VTE.

Conclusion

Women 18–64 years are at low risk of recurrent VTE. Women with hormone associated VTE had a lower risk of recurrence than women with unprovoked VTE, but not as low as surgery/cast provoked VTE.     

Thromboprophylaxis patterns,risk factors,and outcomes of care in the medically ill patient population

Introduction

Medically ill, hospitalized patients are at increased risk for venous thromboembolism (VTE) after discharge. This study aimed to examine thromboprophylaxis patterns, risk factors, and post-discharge outcomes.

Methods

This was a retrospective claims analysis involving administrative claims data and in-patient data abstracted from a sample of hospital charts. Patients aged ≥ 40 years hospitalized for ≥ 2 days for nonsurgical reasons between 2005 and 2009 were included. Hospital chart data were abstracted for a random sample of patients without evidence of anticoagulant use at 30 days post-discharge. The combined data determined whether in-patient thromboprophylaxis (anticoagulant or mechanical prophylaxis) reduces risk of VTE at 90 days post-discharge. Hazard ratios (HR) and odds ratios (OR) were calculated using Cox proportional hazard models and logistic regression.

Results

Of 141,628 patients in the claims analysis, 3.9% received anticoagulants (3.6% warfarin). VTE, rehospitalization, and mortality rates were 1.9%, 17.2%, and 6.2%, respectively. The strongest predictors of post-discharge VTE were history of VTE (HR = 4.0, 95% confidence interval [CI]: 3.3-4.8), and rehospitalization (HR = 3.9, 95% CI: 3.6-4.3). Of 504 medical charts, 209 (41.5%) reported in-patient thromboprophylaxis. There was no statistically significant difference in post-discharge VTE rates between patients who did and did not receive in-patient thromboprophylaxis. All-cause mortality was greater among patients without use of VTE prophylaxis.

Conclusion

Utilization rates of in-hospital and post-discharge VTE prophylaxis were low. In-hospital VTE prophylaxis did not reduce the risk of post-discharge VTE in the absence of post-discharge anticoagulation. Combined in-patient and post-discharge thromboprophylaxis lowered the odds of short-term, all-cause post-discharge mortality.