Statin use and mortality in patients with deep vein thrombosis. Data from the RIETE Registry.

BACKGROUND: The association between statin use and mortality in patients with deep vein thrombosis (DVT) has not been rigorously evaluated. METHODS: We used the data in the RIETE registry to examine the association between statin use and mortality at 3 months. We used mixed effects survival models accounting for clinical covariates and clustering of patients in enrolling centers. RESULTS: From January 2009 through April 2022, there were 46,440 patients with isolated DVT in RIETE (in the lower-limbs 42,291, in the upper limbs 4149). Of these, 21 % and 18 %, respectively, were using statins. Statin users were older than non-users (72 ± 12 vs. 62 ± 18 years), and more likely had diabetes, hypertension, prior myocardial infarction or ischemic stroke, or were receiving antiplatelets. The 3-month mortality rates were: 6.0 % vs. 5.8 %, respectively. On multilevel multivariable analysis, the adjusted hazard ratio (aHR) for all-cause death in statin users vs. non-users was 0.77 (95%CI: 0.69-0.86). The 3-month risk of death in statin users was significantly lower than in non-users in patients with upper-limb DVT (aHR: 0.81; 95%CI: 0.72-0.91), distal lower-limb DVT (aHR: 0.48; 95%CI: 0.32-0.72), or proximal lower-limb DVT (aHR: 0.69; 95%CI: 0.50-0.95), and in those receiving simvastatin (aHR: 0.73; 95%CI: 0.60-0.90), atorvastatin (aHR: 0.70; 95%CI: 0.59-0.85), or rosuvastatin (aHR: 0.47; 95%CI: 0.27-0.80). Major bleeding, used as a falsification endpoint, did not show an association with use of statins at 3-month follow-up. CONCLUSIONS: Statin users with isolated DVT were at significantly lower risk for death at 3 months than non-users.

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism.

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.

Prognostic Significance of Concomitant Superficial Vein Thrombosis in Patients with Deep Vein Thrombosis of the Lower Limbs.

BACKGROUND: The prognostic significance of concomitant superficial vein thrombosis (SVT) in patients with lower-limb deep vein thrombosis (DVT) has not been consistently evaluated. METHODS: We used the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) registry to compare the rates of subsequent pulmonary embolism (PE), recurrent DVT, major bleeding or death in patients with lower-limb DVT, according to the presence or absence of concomitant SVT. RESULTS: From March 2015 to May 2020, there were 8,743 patients with lower-limb DVT. Of these, 745 (8.5%) had concomitant SVT. Most patients (97.4% in both subgroups) received anticoagulant therapy (median duration: 138 vs. 147 days). During follow-up (median: 193 vs. 210 days), 156 (1.8%) patients developed subsequent PE, 336 (3.8%) had recurrent DVT, 201 (2.3%) had major bleeding and 844 (9.7%) died. Patients with concomitant SVT had a higher rate of subsequent PE (rate ratio [RR]: 2.11; 95% confidence interval [95%CI]: 1.33-3.24) than those with isolated DVT, with no significant differences in the rates of recurrent DVT (RR: 0.80; 95%CI: 0.50-1.21), major bleeding (RR: 0.77; 95%CI: 0.41-1.33) or death (RR: 0.81; 95%CI: 0.61-1.06). On multivariable analysis, patients with DVT and SVT concomitantly were at increased risk of subsequent PE during anticoagulation (adjusted hazard ratio [HR]: 2.23; 95%CI: 1.22-4.05) and also during the entire follow-up period (adjusted HR: 2.33; 95%CI: 1.49-3.66). CONCLUSION: Patients with lower-limb DVT and SVT concomitantly are at increased risk of developing PE. Further studies are needed to externally validate our findings and to determine if these patients could benefit from a different management strategy.

Severe renal impairment and risk of bleeding during anticoagulation for venous thromboembolism.

BACKGROUND: Detection of severe renal impairment in patients with venous thromboembolism (VTE) is mandatory both for selecting anticoagulant therapy and for evaluating major bleeding risk, increased by severe renal impairment. OBJECTIVES: To determine whether the Cockcroft and Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas identify severe renal impairment in the same VTE patients presenting the same risk of major bleeding. PATIENTS/METHODS: We compared clinical characteristics and outcomes during the first 3 months of anticoagulation between VTE patients in the RIETE registry with severe renal impairment according to the CG and/or CKD-EPI formula (estimated glomerular filtration rate <30 mL/min and <30 mL/min/1.73 m2 , respectively). The primary outcome was major bleeding. RESULTS: Up to October 2017, 41 796 patients were included in RIETE. Among the 4676 patients with severe renal impairment according to at least one of the formulas, this was not confirmed by the other formula in 1904 (40.7%). Major bleeding risk was increased in every patient subgroup with severe renal impairment vs patients without this condition (CG or CKD-EPI < 30: odds ratio [OR] = 2.26, 95% confidence interval [CI 2.01-2.53], only CG < 30: OR = 1.72, 95% CI [1.37-2.13], only CKD-EPI < 30: OR = 2.34, 95% CI [1.77-3.05], CG+CKD-EPI < 30: OR = 2.47, 95% CI [2.16-2.83], all vs CG+CKD-EPI > 30). CONCLUSION: The CG and CKD-EPI formulas identify different subgroups of patients with severe renal impairment, leading to discordant results in 40.7% of these patients. Irrespective of the formula used for their identification, patients with severe renal impairment have a higher risk of major bleeding under anticoagulant therapy.

Anticoagulación del paciente anciano pluripatológico con fibrilación auricular no valvular: papel del rivaroxabán / Anticoagulation in elderly patients with multiple comorbidities and nonvalvular atrial fibrillation: the role of rivaroxaban

La fibrilación auricular es muy frecuente en el paciente anciano. Aunque existe una amplia experiencia con los antagonistas de la vitamina K, el empleo de estos fármacos en el paciente anciano presenta numerosas limitaciones, con una mayor susceptibilidad a las hemorragias y un peor control de la anticoagulación que en la población general. Los anticoagulantes orales de acción directa han demostrado ser una mejor alternativa terapéutica para los pacientes ancianos, no solo por su mayor simplicidad de uso, sino por sus mayores eficacia y seguridad en comparación con los antagonistas de la vitamina K, con datos que en general concuerdan con los ensayos clínicos fundamentales. Sin embargo, en el paciente anciano hay una tendencia al uso de dosis inadecuadas, generalmente por infradosificación, sobre todo con algunos de ellos, lo que conlleva una menor protección contra los ictus, sin una clara ventaja antihemorrágica. El rivaroxabán se ha estudiado ampliamente en la población anciana y no solo en ensayos clínicos, sino también en multitud de estudios en la práctica clínica real, con datos muy consistentes. En estos estudios, en comparación con los antagonistas de la vitamina K, se ha demostrado que el rivaroxabán reduce el riesgo de ictus sin un incremento de las hemorragias mortales, con lo que tiene un beneficio clínico neto favorable en la población con fibrilación auricular no valvular con mayor riesgo tromboembólico

Atrial fibrillation is common in elderly patients. Although vitamin K antagonists have been widely used for many years, they have a number of limitations in elderly patients, who are particularly susceptible to bleeding and in whom anticoagulation control is poorer than in the general population. Direct oral anticoagulants have been shown to be a better therapeutic option for these patients, not only because they are simpler to use, but also because they are more effective and safer than vitamin K antagonists. Moreover, their performance in practice is generally consistent with that in pivotal clinical trials. Nevertheless, there is a tendency to administer inappropriate doses to elderly patients, generally underdosing, particularly in certain subgroups. This can result in less protection against stroke without any clear reduction in bleeding risk. Rivaroxaban has been widely studied in the elderly population, not only in clinical trials, but also in a range of studies in routine clinical practice - findings have been highly consistent. According to these studies, and compared to vitamin K antagonists, rivaroxaban reduces the risk of stroke without increasing the rate of fatal bleeding, with a net clinical benefit in patients with nonvalvular atrial fibrillation and a high thromboembolic risk

Statin and all-cause mortality in patients receiving anticoagulant therapy for venous thromboembolism. Data from the RIETE registry.

BACKGROUND: The clinical outcomes during the course of anticoagulation in patients with venous thromboembolism (VTE) using statins remain controversial. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the risk for VTE recurrences, major bleeding or death during anticoagulation, according to the use of statins at baseline. We used propensity score-matching (PSM) to adjust for confounding variables. RESULTS: From February 2009 to January 2018, 32,062 VTE patients were included. Of these, 7,085 (22%) were using statins. Statin users were 10 years older (73±11 vs. 63±19 years, respectively) and more likely to have comorbidities or to be using antiplatelets or corticosteroids at baseline than non-users. During the course of anticoagulation (median, 177 days), 694 patients developed VTE recurrences, 848 bled and 3,169 died (fatal pulmonary embolism 176, fatal bleeding 121). Statin users had a similar rate of VTE recurrences (hazard ratio [HR]: 0.98; 95%CI: 0.82-1.17), a higher rate of major bleeding (HR: 1.29; 95%CI: 1.11-1.50) and a similar mortality rate (HR: 1.01; 95%CI: 0.93-1.10) than non-users. On PSM analysis, statin users had a significantly lower risk for death (HR: 0.62; 95%CI: 0.48-0.79) and a similar risk for VTE recurrences (HR: 0.98; 95%CI: 0.61-1.57) or major bleeding (HR: 0.85; 95%CI: 0.59-1.21) than non-users. CONCLUSIONS: During anticoagulation for VTE, patients using statins at baseline had a lower risk to die than non-users.

Management and outcome of major bleeding in patients receiving vitamin K antagonists for venous thromboembolism.

BACKGROUND: The optimal management of major bleeding in patients receiving vitamin K antagonists (VKA) for venous thromboembolism (VTE) is unclear. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to assess the management and 30-day outcomes after major bleeding in patients receiving VKA for VTE. RESULTS: From January 2013 to December 2017, 267 of 18,416 patients (1.4%) receiving long-term VKA for VTE had a major bleeding (in the gastrointestinal tract 78, intracranial 72, hematoma 50, genitourinary 20, other 47). Overall, 151 patients (57%) received blood transfusion; 110 (41%) vitamin K; 37 (14%) fresh frozen plasma; 29 (11%) pro-haemostatic agents and 20 (7.5%) a vena cava filter. During the first 30 days, 59 patients (22%) died (41 died of bleeding) and 13 (4.9%) had a thrombosis. On multivariable analysis, patients with intracranial bleeding (hazard ratio [HR]: 4.58; 95%CI: 2.40-8.72) and those with renal insufficiency at baseline (HR: 2.73; 95%CI: 1.45-5.15) had an increased mortality risk, whereas those receiving vitamin K had a lower risk (HR: 0.47; 0.24-0.92). On the other hand, patients receiving fresh frozen plasma were at increased risk for thrombotic events (HR: 4.22; 95%CI: 1.25-14.3). CONCLUSIONS: Major bleeding in VTE patients receiving VKA carries a high mortality rate. Intracranial bleeding and renal insufficiency increased the risk. Fresh frozen plasma seems to increase this risk for recurrent VTE.

Arterial Ischemic Events Are a Major Complication in Cancer Patients with Venous Thromboembolism.

BACKGROUND: Venous thromboembolism is common in patients with malignancies, affecting up to 10% of this patient population. The association between arterial ischemic events and venous thromboembolism also has been established. However, the influence of arterial ischemic events on outcomes in cancer patients with venous thromboembolism has not been fully determined. METHODS: The current study analyzed clinical characteristics, time course, risk factors, incidence and severity of venous thromboembolism recurrences, arterial ischemic events and major bleeding in 5717 patients with active cancer and venous thromboembolism recruited into RIETE (multi-center prospective registry of patients with objectively confirmed venous thromboembolism). RESULTS: During the anticoagulation course (median 7.3 months), 499 (8.7%) patients developed venous thromboembolism recurrences, 63 (1.1%) developed arterial events, and 346 (6.1%) suffered from major bleeding. Overall, major bleeding and arterial events appeared earlier (median 35 and 36 days, respectively) than venous thromboembolism recurrences (median 97 days). Thirty-day mortality rates after each event were: 20% after recurrent pulmonary embolism, 13% after recurrent deep vein thrombosis, 41% after major bleeding, 40% after myocardial infarction, 64% after ischemic stroke, and 83% after lower limb amputation. Bleeding was the leading cause of death (67 fatal bleeds), whereas cumulative mortality due to arterial ischemic events (n = 27) was similar to that related to pulmonary embolism recurrences (n = 26). CONCLUSIONS: In this study, arterial ischemic events and major bleeding appeared early after venous thromboembolism in patients with active cancer and were among frequent causes of their deaths. The risk and severity of arterial events need to be considered in this clinical setting.

Platelet Count and Major Bleeding in Patients Receiving Vitamin K Antagonists for Acute Venous Thromboembolism, Findings From Real World Clinical Practice.

The outcome of patients with acute venous thromboembolism (VTE) and abnormal platelet count (PlC) at baseline has not been consistently studied. In real-world clinical practice, a number of patients with abnormal PlC receive vitamin K antagonists (VKAs) to treat acute VTE despite their higher risk of bleeding.We used the Registro Informatizado de Enfermedad TromboEmbólica registry database to compare the rate of major bleeding in patients receiving VKA for long-term therapy of acute VTE according to PlC levels at baseline. Patients were categorized as having very low (<100,000/µL), low (100,000-150,000/µL), normal (150,000-300,000/µL), high (300,000-450,000/µL), or very high (>450,000/µL) PlC at baseline.Of 55,369 patients recruited as of January 2015, 37,000 (67%) received long-term therapy with VKA. Of these, 611 patients (1.6%) had very low PlC, 4006 (10.8%) had low PlC, 25,598 (69%) had normal PlC, 5801 (15.6%) had high PlC, and 984 (2.6%) had very high PlC at baseline. During the course of VKA therapy (mean, 192 days), there were no differences in the duration or intensity (as measured by international normalized ratio levels) of treatment between subgroups. The rate of major bleeding was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, 0.34%, and 0.50%, respectively. Patients with very low or very high PlC levels were more likely to have severe comorbidities.We found a nonlinear "U-shaped" relationship between PlC at baseline and major bleeding during therapy with VKA for VTE. Consistent alteration of PlC values at baseline suggested a greater frailty.

Smoking cessation and outcome in stable outpatients with coronary, cerebrovascular, or peripheral artery disease.

BACKGROUND: The influence of smoking cessation on outcome in patients with peripheral arterial disease (PAD) has not been thoroughly studied. METHODS: FRENA is an ongoing registry of stable outpatients with symptomatic coronary artery disease (CAD), cerebrovascular disease (CVD), or PAD. We compared the mortality rate of those who quit vs. those who continued smoking. RESULTS: As of December 2010, 3523 patients were recruited, of whom 1182 (34%) were current smokers. Of these, 475 patients (40%) had CAD, 240 (20%) had CVD, and 467 (40%) had PAD. In all, 512 patients (43%) quit smoking. Over a mean follow-up of 14 months, 32 patients (2.7%) died and 95 (8.0%) had subsequent ischaemic events (myocardial infarction 32, ischaemic stroke 20, critical limb ischaemia/disabling claudication 53). In patients with CAD, the mortality rate was significantly lower in recent quitters (0.77 vs. 3.73 deaths per 100 patient-years; p = 0.013) than in persistent smokers. No quitter with CVD died (0.0 vs. 2.18 deaths; p = 0.092); but in patients with PAD there was a trend towards a higher mortality in quitters than in those who continued smoking (4.29 vs. 2.27 deaths; p = 0.357). On multivariate analysis, the relative risk for death in quitters was 0.20 (95% CI 0.05-0.75) in patients with CAD, 0.0 in those with CVD, and 1.83 (95% CI 0.65-5.15) in those with PAD. CONCLUSIONS: Smoking cessation was associated with a significant decrease in mortality in patients with CAD, a non-significant decrease in those with CVD, and a non-significant increase in those with PAD.