Polypharmacy is associated with an increased risk of bleeding in elderly patients with venous thromboembolism.

BACKGROUND: Polypharmacy, defined as the concomitant use of multiple medications, is very common in the elderly and may trigger drug-drug interactions and increase the risk of falls in patients receiving vitamin K antagonists. OBJECTIVE: To examine whether polypharmacy increases the risk of bleeding in elderly patients who receive vitamin K antagonists for acute venous thromboembolism (VTE). DESIGN: We used a prospective cohort study. PARTICIPANTS: In a multicenter Swiss cohort, we studied 830 patients aged ≥ 65 years with VTE. MAIN MEASURES: We defined polypharmacy as the prescription of more than four different drugs. We assessed the association between polypharmacy and the time to a first major and clinically relevant non-major bleeding, accounting for the competing risk of death. We adjusted for known bleeding risk factors (age, gender, pulmonary embolism, active cancer, arterial hypertension, cardiac disease, cerebrovascular disease, chronic liver and renal disease, diabetes mellitus, history of major bleeding, recent surgery, anemia, thrombocytopenia) and periods of vitamin K antagonist treatment as a time-varying covariate. KEY RESULTS: Overall, 413 (49.8 %) patients had polypharmacy. The mean follow-up duration was 17.8 months. Patients with polypharmacy had a significantly higher incidence of major (9.0 vs. 4.1 events/100 patient-years; incidence rate ratio [IRR] 2.18, 95 % confidence interval [CI] 1.32-3.68) and clinically relevant non-major bleeding (14.8 vs. 8.0 events/100 patient-years; IRR 1.85, 95 % CI 1.27-2.71) than patients without polypharmacy. After adjustment, polypharmacy was significantly associated with major (sub-hazard ratio [SHR] 1.83, 95 % CI 1.03-3.25) and clinically relevant non-major bleeding (SHR 1.60, 95 % CI 1.06-2.42). CONCLUSIONS: Polypharmacy is associated with an increased risk of both major and clinically relevant non-major bleeding in elderly patients receiving vitamin K antagonists for VTE.

["And zebras do exist after all"! : Pulmonary nocardiosis: case series and overview]. / "Und Zebras gibt es doch!" : Pulmonale Nokardiose: Fallserie und Übersicht.

Nocardiosis is a rare disease that occurs primarily in patients with predisposing factors (immunosuppression/chronic lung disease). It is caused by aerobic, Gram-positive bacteria that are ubiquitous in soil. Cutaneous and pulmonary manifestations are most common, but disseminated forms also occur. In terms of treatment, long-term antibiotic therapy is usually necessary. The prognosis for the cutaneous or pulmonary form is generally good.

The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology.

Venous thromboembolism (VTE) is common and has a high impact on morbidity, mortality, and costs of care. Although most of the patients with VTE are aged ≥65 years, there is little data about the medical outcomes in the elderly with VTE. The Swiss Cohort of Elderly Patients with VTE (SWITCO65+) is a prospective multicenter cohort study of in- and outpatients aged ≥65 years with acute VTE from all five Swiss university and four high-volume non-university hospitals. The goal is to examine which clinical and biological factors and processes of care drive short- and long-term medical outcomes, health-related quality of life, and medical resource utilization in elderly patients with acute VTE. The cohort also includes a large biobank with biological material from each participant. From September 2009 to March 2012, 1,863 elderly patients with VTE were screened and 1003 (53.8%) were enrolled in the cohort. Overall, 51.7% of patients were aged ≥75 years and 52.7% were men. By October 16, 2012, after an average follow-up time of 512 days, 799 (79.7%) patients were still actively participating. SWITCO65+ is a unique opportunity to study short- and long-term outcomes in elderly patients with VTE. The Steering Committee encourages national and international collaborative research projects related to SWITCO65+, including sharing anonymized data and biological samples.

Thrombophilia and outcomes of venous thromboembolism in older patients.

Background: Limited data exist on thrombophilic risk factors and clinical outcomes in the elderly with venous thromboembolism (VTE). Objectives: To describe the prevalence of laboratory thrombophilic risk factors and their association with VTE recurrence or death in a cohort of elderly people with VTE. Methods: In 240 patients aged ≥65 years with acute VTE without active cancer or an indication for extended anticoagulation, we performed laboratory thrombophilia testing 1 year after the index VTE. Recurrence or death was assessed during the 2-year follow-up. Results: A total of 78% of patients had ≥1 laboratory thrombophilic risk factor(s). Elevated levels of von Willebrand factor, homocysteine, coagulant activity of factor VIII (FVIII:C), fibrinogen, FIX:C, and low antithrombin activity were the most prevalent risk factors (43%, 30%, 15%, 14%, 13%, and 11%, respectively). Additionally, 16.2% of patients experienced VTE recurrence and 5.8% of patients died. Patients with a von Willebrand factor of >182%, FVIII:C level >200%, homocysteine level >15µmol/L, or lupus anticoagulant had a significantly higher rate of recurrence than those without these risk factors (15.0 vs. 6.1 [P = .006], 23.5 vs. 8.2 [P = .01], 17.0 vs. 6.8 [P = .006], and 89.5 vs. 9.2 [P = .02] events per 100 patient-years, respectively). Furthermore, patients with a high fibrinogen level or hyperhomocysteinemia with a homocysteine level ≥30 µmol/L had significantly higher mortality than patients with normal levels (18.5 vs. 2.8 [P = .049] and 13.6 vs. 2 [P = .002] deaths per 100 patient-years, respectively). After adjustments for relevant confounders, these associations remained unchanged. Conclusion: Laboratory thrombophilic risk factors are common in elderly people with VTE and allow for the identification of a population at the risk of worse clinical outcomes.

Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.

BACKGROUND: Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care. METHODS: We undertook an open-label, randomised non-inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2-4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital ≤24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (≥5 days) followed by oral anticoagulation (≥90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00425542. FINDINGS: Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0·6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2·7%; p=0·011). Only one (0·6%) patient in each treatment group died within 90 days (95% UCL 2·1%; p=0·005), and two (1·2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3·6%; p=0·031). By 90 days, three (1·8%) outpatients but no inpatients had developed major bleeding (95% UCL 4·5%; p=0·086). Mean length of stay was 0·5 days (SD 1·0) for outpatients and 3·9 days (SD 3·1) for inpatients. INTERPRETATION: In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care. FUNDING: Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres.

Dronedarone reduces arterial thrombus formation.

Dronedarone has been associated with a reduced number of first hospitalisation due to acute coronary syndromes. Whether this is only due to the reduction in ventricular heart rate and blood pressure or whether other effects of dronedarone may be involved is currently elusive. This study was designed to investigate the role of dronedarone in arterial thrombus formation. C57Bl/6 mice were treated with dronedarone and arterial thrombosis was investigated using a mouse photochemical injury model. Dronedarone inhibited carotid artery thrombus formation in vivo (P < 0.05). Thrombin- and collagen-induced platelet aggregation was impaired in dronedarone-treated mice (P < 0.05), and expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic system, was reduced in the arterial wall (P < 0.05). In contrast, the level of tissue factor (TF), the main trigger of the coagulation cascade, and that of its physiological inhibitor, TF pathway inhibitor, did not differ. Similarly, coagulation times as measured by prothrombin time and activated partial thromboplastin time were comparable between the two groups. Dronedarone inhibits thrombus formation in vivo through inhibition of platelet aggregation and PAI1 expression. This effect occurs within the range of dronedarone concentrations measured in patients, and may represent a beneficial pleiotropic effect of this drug.

Do Factor V Leiden and Prothrombin G20210A Mutations Predict Recurrent Venous Thromboembolism in Older Patients?

BACKGROUND: The value of genetic thrombophilia testing in elderly patients with an unprovoked venous thromboembolism is unclear. We assessed whether the Factor V Leiden and the prothrombin G20210A mutation are associated with recurrent venous thromboembolism in elderly patients in a prospective multicenter cohort study. METHODS: We genotyped the Factor V Leiden and the prothrombin G20210A mutation in 354 consecutive in- and outpatients aged ≥65 years with a first unprovoked venous thromboembolism from 9 Swiss hospitals. Patients and managing physicians were blinded to testing results. The outcome was recurrent symptomatic venous thromboembolism during follow-up. We examined the association between the Factor V Leiden and the prothrombin G20210A mutation and venous thromboembolism recurrence using competing risk regression, adjusting for age, sex, and periods of anticoagulation as a time-varying covariate. RESULTS: Overall, 9.0% of patients had a Factor V Leiden and 3.7% had a prothrombin G20210A mutation. At 36 months of follow-up, patients with a Factor V Leiden and a prothrombin G20210A mutation had a cumulative incidence of recurrent venous thromboembolism of 12.9% (95% confidence interval [CI], 5.1%-30.8%) and 18.5% (95% CI, 4.9%-56.5%), respectively, compared with 16.7% (95% CI, 12.5%-22.1%) of patients without mutation (P = .91 by the log-rank test). After adjustment, neither the Factor V Leiden (sub-hazard ratio 0.98; 95% CI, 0.35-2.77) nor the prothrombin G20210A mutation (sub-hazard ratio 1.15; 95% CI, 0.25-5.19) was associated with recurrent venous thromboembolism. CONCLUSION: Our results suggest that testing for genetic thrombophilia may not be beneficial in elderly patients with a first unprovoked venous thromboembolism.

Derivation and validation of a novel bleeding risk score for elderly patients with venous thromboembolism on extended anticoagulation.

Existing clinical scores do not perform well in predicting bleeding in elderly patients with acute venous thromboembolism (VTE). We sought to derive an easy-to-use clinical score to help physicians identify elderly patients with VTE who are at high-risk of bleeding during extended anticoagulation (>3 months). Our derivation sample included 743 patients aged ≥65 years with VTE who were enrolled in a prospective multicenter cohort study. All patients received extended anticoagulation with vitamin K antagonists. We derived our score using competing risk regression, with the time to a first major bleeding up to 36 months of extended anticoagulation as the outcome, and 17 candidate variables as predictors. We used bootstrapping methods for internal validation. Sixty-six (9 %) patients suffered major bleeding. The clinical score is based on seven clinical factors (previous bleeding, active cancer, low physical activity, anemia, thrombocytopenia, antiplatelet drugs/NSAIDs, and poor INR control). Overall, 48 % of patients were classified as low-risk, 37 % as moderate-risk, and 15 % as high-risk of bleeding. The rate of major bleeding was 1.4 events in low-risk, 5.0 events in moderate-risk, and 12.2 events per 100 patient-years in high-risk patients. The c-statistic was 0.78 at 3 months and 0.71 at 36 months of extended anticoagulation. Model calibration was excellent (p=0.93). Internal validation showed similar results. This simple clinical score accurately identified elderly patients with VTE who are at high risk of major bleeding and who may not benefit from extended anticoagulation. Further validation of the score is important before its implementation into practice. The study is registered to https://clinicaltrials.gov as NCT00973596.

The MAP kinase JNK2 mediates cigarette smoke-induced arterial thrombosis.

Despite public awareness of its deleterious effects, smoking remains a major cause of death. Indeed, it is a risk factor for atherothrombotic complications and in line with this, the introduction of smoking ban in public areas reduced smoking-associated cardiovascular complications. Nonetheless, smoking remains a major concern, and molecular mechanisms by which it causes cardiovascular disease are not known. Peripheral blood monocytes from healthy smokers displayed increased JNK2 and tissue factor (TF) gene expression compared to non-smokers (n=15, p<0.05). Similarly, human aortic endothelial cells exposed to cigarette smoke total particulate matter (CS-TPM) revealed increased TF expression mediated by JNK2 (n=4; p<0.05). Wild-type and JNK2-/- mice were exposed to cigarette smoke for two weeks after which arterial thrombosis was investigated. Wild-type mice exposed to smoke displayed reduced time to thrombotic arterial occlusion (n=8; p<0.05) and increased tissue factor activity (n=7; p<0.05) as compared to wild-type controls (n=6), while JNK2-/-mice exposed to smoke maintained an unaltered thrombotic potential (n=8; p=NS) and tissue factor activity (n=8) comparable to that of JNK2-/- and wild-type controls (n=6; p=NS). Smoking caused an increased production of reactive oxygen species (ROS) in wild-type but not in JNK2-/- mice (n=7; p<0.05 for wild-type mice and n=5-6; p=NS for JNK2-/- mice). In conclusion, the MAP kinase JNK2 mediates cigarette smoke-induced TF activation, arterial thrombosis and ROS production. These results underscore a major role of JNK2 in smoke-mediated thrombus formation and may offer an attractive target to prevent smoke-related thrombosis in those subjects which do not manage quitting.

The adherence to initial processes of care in elderly patients with acute venous thromboembolism.

BACKGROUND: We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence. METHODS: We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence. RESULTS: Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence. CONCLUSIONS: Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

Swiss results from a global observational study of venous thromboembolism risk and prophylaxis use in the acute care hospital setting: analysis from the ENDORSE study.

BACKGROUND: The aim of the present analysis from the epidemiologic international day for the evaluation of patients at risk for venous thromboembolism (VTE) in the acute hospital care setting (ENDORSE) study was to evaluate the prevalence of VTE risk in acute care hospitals and the proportion of at-risk medical and surgical patients who receive recommended prophylaxis in Switzerland. METHODS: All patients (age >or=40 years) admitted to a medical ward or those (age >or=18 years) admitted to a surgical ward in ten randomly selected Swiss hospitals were assessed for risk of VTE. The 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines were used to assess VTE risk and to determine whether patients were receiving recommended thromboprophylaxis. RESULTS: 2000 patients were eligible; of these 1153 (58%) were in surgical wards, and 847 (42%) in medical wards. According to the ACCP criteria, the proportion of surgical patients at VTE risk was similar in Switzerland (68%, between hospital range 48-86%) in comparison to the global ENDORSE study (64%) (p = 0.296). The rate of at-risk medical patients was lower in Switzerland (21%, range 3-44%) than in the global study (42%) (p <0.001). The proportion of at-risk surgical patients with ACCP-recommended VTE prophylaxis was higher in Switzerland (81%, between-hospital range 76-93%) than in the global study (59%) (p <0.001). Among medical patients at risk, the use of recommended thromboprophylaxis was higher in Switzerland (61%, between-hospital range 0-84%) than in the global ENDORSE (40%) (p <0.001). However 56% of the patients with cancer, 41% with major trauma, and 29% undergoing vascular surgery did not receive any recommended prophylaxis. Among surgical patients at risk, the use of ACCP-recommended prophylaxis was lower in academic (77%) vs. non-academic (86%) institutions (p = 0.0025). CONCLUSIONS: In Switzerland, although the rate of recommended thromboprophylaxis is higher than in many countries, it is still improvable in medical patients at risk according to the ACCP guidelines. Consequently, hospital wide strategies for systematic risk factor assessment and implementation of practical tools to ensure appropriate use of prophylaxis in patients at VTE risk are required.