Alicia Lorenzo

An Acenocoumarol Dosing Algorithm Using Clinical and Pharmacogenetic Data in Spanish Patients with Thromboembolic Disease

Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; nu200a=u200a117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (nu200a=u200a30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.

Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis

BACKGROUNDnThe risk of patients dying of pulmonary embolism (PE) or bleeding during the treatment of deep vein thrombosis (DVT), and whether these risks are influenced by patient age, has not been thoroughly studied.nnnMETHODSnWe used data from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) to assess the risk of fatal PE and fatal bleeding in 16,199 patients with lower limb DVT (without symptomatic PE at the time of inclusion) during the 3 months after diagnosis, with patients categorized according to age.nnnRESULTSnDuring the 3 months of anticoagulant treatment, there were 31 fatal PEs (0.19%) and 83 fatal hemorrhages (0.51%). During the first 7 days of therapy, the frequency of fatal PEs was similar to that of fatal bleeding (12 vs 14 deaths, respectively; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.39-1.87). However, from days 8 to 90, the frequency of fatal bleeding was greater than that of fatal PE (69 vs 19 deaths; OR, 3.64; 95% CI, 2.22-6.20). The higher frequency of fatal bleeding compared with fatal PE from days 8 to 90 appeared to be confined to patients who were aged ≥ 60 years. Multivariate analysis showed that patient age was independently associated with an increased risk of death from bleeding during the first 3 months: every 10 years the OR increased by 1.37 (95% CI, 1.12-1.67).nnnCONCLUSIONSnDuring the first week of treatment, the risk of fatal bleeding and fatal PE were similar. Then, particularly in patients who were aged ≥ 60 years, the risk of dying from bleeding exceeded the risk of dying from PE.

Clinical characteristics and outcome of inpatients versus outpatients with venous thromboembolism Findings from the RIETE Registry

BACKGROUNDnPatients with venous thromboembolism (VTE) treated with anticoagulants are at risk of death from pulmonary embolism (PE) and/or bleeding. However, whether patients who develop VTE in hospital have a higher complication rate than those who develop VTE in an outpatient setting is unclear.nnnPATIENTS AND METHODSnRIETE is an ongoing, prospective registry of consecutive patients with acute, objectively confirmed, symptomatic VTE. We compared the 3-month incidence of fatal PE and fatal bleeding in patients in whom the VTE had developed while in hospital for another medical condition (inpatients) with those who presented to the emergency ward because of VTE (outpatients).nnnRESULTSnUp to April 2008, 22,133 patients with acute VTE were enrolled: 10,461 (47%) presented with PE, 11,672 with deep vein thrombosis. Overall, 6445 (29%) were inpatients. During the study period, those who developed VTE as inpatients had a significantly higher incidence of fatal PE (2.1% vs. 1.5%; odds ratio: 1.4; 95% CI: 1.1-1.7), overall death (7.0% vs. 5.4%; odds ratio: 1.3; 95% CI: 1.2-1.5), and major bleeding (2.9% vs. 2.1%; odds ratio: 1.4; 95% CI: 1.1-1.6) than outpatients. The incidence of fatal bleeding was not significantly increased (0.7% vs. 0.5%; odds ratio: 1.2; 95% CI: 0.9-1.8). In multivariable analysis, inpatient status was significantly associated with a higher risk for fatal PE (odds ratio: 1.3; 95% CI: 1.1-1.7).nnnCONCLUSIONSnVTE occurring in hospitalized patients carries a significantly higher risk for death of PE than in outpatients, underscoring the importance of VTE prevention strategies in the hospital setting.

Association Between Obstructive Sleep Apnea and Pulmonary Embolism

OBJECTIVESnTo compare the prevalence of obstructive sleep apnea (OSA) in patients with pulmonary embolism (PE) with a sex-, age-, and body mass index (BMI)-matched, population-based control group and to assess the association between OSA and PE.nnnMETHODSnWe performed a case-control study from October 1, 2006, through November 30, 2009. We included 107 patients with PE and a control group (n=102) without PE in University Hospitals Son Espases and La Paz in Spain. Variables included in the analysis were medical history, anthropometric variables (weight, height, BMI, and neck circumference), Epworth Sleepiness Scale score, home respiratory polygraphy, basic biochemical profile and hemogram, spirometry, and physical activity.nnnRESULTSnThe mean ± SD apnea-hypopnea index (AHI) was significantly higher in patients with PE than population controls (21.2±20.6 vs 11.5±15.9 h(-1); P<.001). The presence of an AHI greater than 5 h(-1) and hypersomnolence (Epworth Sleepiness Scale score ≥11) was more frequent in PE patients than in controls (14.0% vs 4.9%; P=.0002). A crude model analysis by several cutoffs revealed that the AHI was significantly associated with PE. After adjustment for age, sex, smoking, BMI, lung function, and all known PE risk factors, the odds ratio for PE was 3.7 (95% CI, 1.3-10.5; P=.01).nnnCONCLUSIONnA higher prevalence of OSA was detected in patients diagnosed as having acute PE than controls. This study identified a significant and independent association between OSA and PE.

High D-dimer levels after stopping anticoagulants in pulmonary embolism with sleep apnoea

Obstructive sleep apnoea is a risk factor for pulmonary embolism. Elevated D-dimer levels and other biomarkers are associated with recurrent pulmonary embolism. The objectives were to compare the frequency of elevated D-dimer levels (>500u2005ng·mL−1) and further coagulation biomarkers after oral anticoagulation withdrawal in pulmonary embolism patients, with and without obstructive sleep apnoea, including two control groups without pulmonary embolism. We performed home respiratory polygraphy. We also measured basic biochemical profile and haemogram, and coagulation biomarkers (D-dimer, prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor 1, and soluble P-selectin). 64 (74.4%) of the pulmonary embolism cases and 41 (46.11%) of the controls without pulmonary embolism had obstructive sleep apnoea. Plasmatic D-dimer was higher in PE patients with OSA than in those without obstructive sleep apnoea. D-dimer levels were significantly correlated with apnoea–hypopnoea index, and nocturnal hypoxia. There were more patients with high D-dimer after stopping anticoagulants in those with pulmonary embolism and obstructive sleep apnoea compared with PE without obstructive sleep apnoea (35.4% versus 19.0%, p=0.003). Apnoea–hypopnoea index was independently associated with high D-dimer. Pulmonary embolism patients with obstructive sleep apnoea had higher rates of elevated D-dimer levels after anticoagulation discontinuation for pulmonary embolism than in patients without obstructive sleep apnoea and, therefore, higher procoagulant state that might increase the risk of pulmonary embolism recurrence. Pulmonary embolism patients with sleep apnoea are more likely to have elevated post-anticoagulation plasma D-dimer http://ow.ly/NHoiu

Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy.

INTRODUCTIONnPatients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugs may increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis.nnnMETHODSnConsecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course.nnnRESULTSn1178 patients who received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p<0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p<0.05) or death (23.6 vs. 13.9 deaths per 100 patients-years; p<0.01). No differences in the rate of major bleeding or recurrent VTE were revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate.nnnCONCLUSIONnConcomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations.

Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism

Essentials Recent randomized trials suggested fewer bleeding events in fragile patients with VTE receiving DOACs. The frequency, clinical characteristics and outcome of these patients have not been reported in real life. Fragile patients with VTE had a higher risk for major bleeding or death and a lower risk for recurrences than non‐fragile.

Analysis of clinical factors affecting the rates of fatal pulmonary embolism and bleeding in cancer patients with venous thromboembolism

Background In cancer patients with symptomatic venous thromboembolism (VTE) (deep-vein thrombosis (DVT) and/or pulmonary embolism (PE)), clinical factors that influence the benefit-risk balance of anticoagulation need to be identified so treatment intensity and duration can be optimally adjusted for the individual patient. Methods Using clinical data for cancer patients with VTE obtained from the RIETE registry, we compared how rates of fatal PE and fatal bleeding during and after anticoagulation vary depending on patients‘ clinical characteristics. Results Data were analysed from the 10,962 cancer patients with VTE (5,740 with PE with or without DVT; 5,222 with DVT alone) in RIETE registry as of March 2016. Fatal PE occurred in 2.18% of patients, while fatal bleedings occurred in 1.55%. During the 12 months from initial VTE, fatal PE was the most common cause of death, after disseminating cancer, and bleeding the fourth most common. In patients initially presenting with PE, fatal PE during anticoagulation was 4-fold more frequent than fatal bleeding (204 vs 51 deaths) and occurred mostly during the first month of treatment (196/223, 88%). In patients initially presenting with DVT, fatal PE was 3-fold lower than fatal bleeding during (25 vs 85 deaths) and after anticoagulation treatment (8 vs 37 deaths). During the 12-month follow-up, other characteristics of cancer patients with VTE were identified as more common in fatal cases of PE and/or bleeding than in surviving cases. Interpretation Baseline clinical characteristics may determine anticoagulation outcomes in cancer patients with VTE and should be further investigated as possible factors for guiding changes in current practices of anticoagulation, such as adjusting anticoagulation intensity and duration in selected patients.

Predictors of Post-Thrombotic Ulcer after Acute DVT: The RIETE Registry

In patients with deep-vein thrombosis (DVT) in the lower limbs, venous ulcer is the most debilitating and end-stage clinical expression of the post-thrombotic syndrome (PTS). To date, risk factors for PTS-related ulcer in DVT patients have not been identified.We used the international observational RIETE registry to assess the evolution of PTS signs and symptoms during a 3-year follow-up period and to identify independent predictors of PTS ulcer at 1 year in patients with acute DVT.Among 1,866 eligible patients, cumulative rates of PTS ulcer at 1, 2 and 3 years were 2.7% (nu2009=u200950), 4.3% (nu2009=u200954) and 7.1% (nu2009=u200960), respectively. The proportion of patients with PTS symptoms at 1, 2 or 3 years remained stable (≈40%), while the proportion of patients with PTS signs increased slightly over time (from 49 to 53%). Prior history of venous thromboembolism (VTE) (odds ratio [OR]u2009=u20095.5 [2.8-10.9]), diabetes (ORu2009=u20092.3 [1.1-4.7]), pre-existing leg varicosities (ORu2009=u20093.2 [1.7-6.1]) and male sex (ORu2009=u20092.5 [1.3-5.1]) independently increased the risk of PTS ulcer at 1 year. Obesity also increased the risk but failed to reach statistical significance (ORu2009=u20091.8 [0.9-3.3]). DVT treatment characteristics (duration or drug) did not influence the risk.Our results evidence that after acute DVT, pre-existing leg varicosities, prior venous thromboembolism, diabetes and male gender independently increased the risk for PTS ulcer. This suggests that clinicians should consider strategies aimed to prevent ulcers in high-risk DVT patients, such as preventing VTE recurrence, use of stockings in those with pre-existing venous insufficiency, careful monitoring of diabetic patients and encouraging weight loss in obese patients.

Gender differences in patients with venous thromboembolism and five common sites of cancer

BACKGROUNDnThe outcome of cancer patients with venous thromboembolism (VTE) may differ according to gender.nnnMETHODSnWe used the RIETE database to compare the rate of VTE recurrences, major bleeding and mortality in patients with lung, colorectal, pancreatic, hematologic or gastric cancer during the course of anticoagulation, according to gender.nnnRESULTSnAs of January 2016, 11,055 patients with active cancer were enrolled: 1,727 had lung cancer, 1,592 colorectal, 840 hematologic, 517 pancreatic and 459 had gastric cancer. Compared with men (N = 3,130), women (N = 2,005) were more likely to have colorectal, pancreatic or hematologic cancer, and less likely to have lung cancer. Most patients (91%) were initially treated with low-molecular-weight heparin (LMWH), but women received higher daily doses per body weight. Then, 66% kept receiving LMWH for long-term therapy. During the course of anticoagulation, 302 patients developed recurrent VTE, 220 bled and 1,749 died. Compared with men, women had a similar rate of VTE recurrences or major bleeding, and a lower mortality (risk ratio [RR]: 0.90; 95% CI: 0.82-0.99). When separately comparing outcomes according to cancer site, women with lung cancer had a lower mortality (RR: 0.79; 95% CI: 0.70-0.92), those with colorectal cancer had a higher mortality (RR: 1.25; 95% CI: 1.02-1.54) and those with gastric cancer had a higher rate of VTE recurrences than men (RR: 2.47; 95% CI: 1.04-5.89).nnnCONCLUSIONSnVTE women with lung, colorectal, pancreatic, haematological or gastric cancer experienced a similar outcome during the course of anticoagulant therapy than men with similar cancers.