Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was 1252.4 ml per year in the nintedanib group and 1293.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P=0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of 120.21 (95% CI, 120.94 to 0.53; P=0.58) and 1.69 (95% CI, 120.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo

Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs

BACKGROUND: One in every three patients with deep vein thrombosis (DVT) in the lower limbs may have silent pulmonary embolism (PE), but its clinical relevance has not been thoroughly studied. METHODS: We used the RIETE Registry data to study patients with proximal DVT and no PE symptoms, but with a systematic search for PE. We compared the outcome of DVT patients with silent PE and those with no PE. RESULTS: Of 2375 patients with DVT, 842 (35%) had silent PE and 1533 had no PE. During the first 15 days of anticoagulation, patients presenting with silent PE had a higher incidence of symptomatic PE events than those with no PE (0.95% vs. 0.13%; P = 0.015), with a similar incidence of major bleeding (0.95% vs. 1.63%; P = 0.09). In patients with silent PE, the incidence of PE events during the first 15 days was equal to the incidence of major bleeding (eight events each), but in those with no PE the incidence of PE events was eight times lower (3 vs. 25 bleeding events). Multivariate analysis confirmed that DVT patients with silent PE had a higher incidence of symptomatic PE events during the first 15 days than those with no PE (odds ratio, 4.80; 95% CI, 1.27-18.1), with no differences in bleeding. CONCLUSIONS: DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events during the first 15 days of anticoagulant therapy. This effect disappeared after 3 months of anticoagulation

Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility.

The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (p(c)=6.6E-4 and p(c)=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (p(c)=1.7E-03 and p(c)=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases

Fondaparinux in the initial and long-term treatment of venous thromboembolism

BACKGROUND: Even in the absence of evidence on its long-term efficacy and safety, a number of patients with venous thromboembolism (VTE) receive long-term therapy with fondaparinux alone in everyday practice. METHODS: We used the Registro Informatizado de Enfermedad Tromboemb\uf3lica (RIETE) registry to compare the rate of VTE recurrences and major bleeding at 10 and 90 days in patients with and without cancer. For long-term therapy, fondaparinux was compared with vitamin K antagonists (VKA) in patients without cancer and with low-molecular-weight heparin (LMWH) in those with cancer. RESULTS: Of 47,378 patients recruited, 46,513 were initially treated with heparin, 865 with fondaparinux. Then, 263 patients (78 with cancer) were treated for at least 3 months with fondaparinux. After propensity-score matching, there were no differences between patients receiving initial therapy with heparin or fondaparinux. Among patients with cancer, there were no differences between fondaparinux and LMWH. Among patients without cancer, the long-term use of fondaparinux was associated with an increased risk of major bleeding (3.24 % vs. 0.95 %, p<0.05). CONCLUSIONS: An unexpected high rate of major bleeding was observed in non-cancer patients treated with long-term fondaparinux. Our small sample does not allow to derive relevant conclusions on the use of fondaparinux in cancer patients

Venous thromboembolism in immobilized patients with dementia. Findings from the RIETE registry.

BACKGROUND: The natural history of venous thromboembolism (VTE) in patients with dementia has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the clinical characteristics, treatment strategies and outcome during the first 3 months after acute VTE in all immobilized patients with dementia. RESULTS: As of August 2011, 37988 patients had been enrolled, of whom 1316 (3.5%) had dementia. Most patients in both subgroups were initially treated with low-molecular-weight heparin (LMWH). Then, 48% of patients with dementia and 25% of those without dementia received LMWH as long-term therapy. During the first 3 months of anticoagulant therapy, patients with dementia had a higher incidence of fatal pulmonary embolism (PE): 4.0% vs. 1.2% (odds ratio: 3.3; 95% CI: 2.5-4.4) and fatal bleeding: 1.4% vs. 0.5% (odds ratio: 2.9; 95% CI: 1.8-4.6) than those without dementia. In demented patients initially presenting with PE, the incidence of fatal PE during the first week outweighed that of fatal bleeding (42 vs. 4 deaths), but from Day 8, the incidence of fatal PE was similar to the incidence of fatal bleeding. In patients initially presenting with deep vein thrombosis (DVT), there were 4 fatal PE and 8 fatal bleeding events. CONCLUSIONS: VTE patients with dementia had a high incidence of fatal PE and fatal bleeding. In those initially presenting with PE, the risk of dying of PE far outweighed that of fatal bleeding. In patients presenting with DVT alone, the risk of fatal PE was lower than that of fatal bleeding

Clinical presentation and outcome of venous thromboembolism in COPD

Chronic obstructive pulmonary disease (COPD) is a moderate risk factor for venous thromboembolism (VTE), but neither the clinical presentation nor the outcome of VTE in COPD patients is well known. The clinical presentation of VTE, namely pulmonary embolism (PE) or deep venous thrombosis (DVT), and the outcome at 3 months (death, recurrent VTE or bleeding) were compared between 2,984 COPD patients and 25,936 non-COPD patients included in the RIETE (Registro Informatizado de la Enfermedad TromboEmb\uf3lica) registry. This ongoing international, multi-centre registry includes patients with proven symptomatic PE or DVT. PE was the more frequent VTE presentation in COPD patients (n = 1,761, 59%). PE presentation was more significantly associated with COPD patients than non-COPD patients (OR 1.64, 95% CI 1.49-1.80). During the 3-month follow-up, mortality (10.8% versus 7.6%), minor bleeding (4.5% versus 2.3%) or first VTE recurrences as PE (1.5% versus 1.1%) were significantly higher in COPD patients than in non-COPD patients. PE was the most common cause of death. COPD patients presented more frequently with PE than DVT. It may explain the worse prognosis of COPD patients, with a higher risk of death, bleeding or VTE recurrences as PE compared with non-COPD patients. Further therapeutic options are needed

Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism

BACKGROUND: The influence of recent immobilization or surgery on mortality in patients with pulmonary embolism (PE) is not well known. METHODS: We used the Registro Informatizado de Enfermedad TromboEmb\uf3lica (RIETE) data to compare the 3-month mortality rate in patients with PE, with patients categorized according to the presence of recent immobilization, recent surgery, or neither. RESULTS: Of 18,028 patients with PE, 4169 (23%) had recent immobilization, 2212 (12%) had recent surgery, and 11,647 (65%) had neither. The all-cause mortality was 10.0% (95% confidence interval [CI] 9.5-10.4), and the PE-related mortality was 2.6% (95% CI 2.4-2.9). One in every two patients who died from PE had recent immobilization (43%) or recent surgery (6.7%). Only 25% of patients with immobilization had received prophylaxis, as compared with 65% of the surgical patients. Fatal PE was more common in patients with recent immobilization (4.9%; 95% CI 4.3-5.6) than in those with surgery (1.4%; 95% CI 1.0-2.0) or those with neither (2.1%; 95% CI 1.8-2.3). On multivariate analysis, patients with immobilization were at increased risk for fatal PE (odds ratio 2.2; 95% CI 1.8-2.7), with no differences being seen between patients immobilized in hospital or in the community. CONCLUSIONS: Forty-three per cent of patients dying from PE had recent immobilization for 654 days. Many of these deaths could have been prevented

Pulmonary embolism and 3-month outcomes in 4036 patients with venous thromboembolism and chronic obstructive pulmonary disease: data from the RIETE registry

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have a modified clinical presentation of venous thromboembolism (VTE) but also a worse prognosis than non-COPD patients with VTE. As it may induce therapeutic modifications, we evaluated the influence of the initial VTE presentation on the 3-month outcomes in COPD patients. METHODS: COPD patients included in the on-going world-wide RIETE Registry were studied. The rate of pulmonary embolism (PE), major bleeding and death during the first 3 months in COPD patients were compared according to their initial clinical presentation (acute PE or deep vein thrombosis (DVT)). RESULTS: Of the 4036 COPD patients included, 2452 (61%; 95% CI: 59.2-62.3) initially presented with PE. PE as the first VTE recurrence occurred in 116 patients, major bleeding in 101 patients and mortality in 443 patients (Fatal PE: first cause of death). Multivariate analysis confirmed that presenting with PE was associated with higher risk of VTE recurrence as PE (OR, 2.04; 95% CI: 1.11-3.72) and higher risk of fatal PE (OR, 7.77; 95% CI: 2.92-15.7). CONCLUSIONS: COPD patients presenting with PE have an increased risk for PE recurrences and fatal PE compared with those presenting with DVT alone. More efficient therapy is needed in this subtype of patients

Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism

BACKGROUND: While the primary therapy for most patients with a pulmonary embolism (PE) consists of anticoagulation, the efficacy of thrombolysis relative to standard therapy remains unclear. METHODS: In this retrospective cohort study of 15,944 patients with an objectively confirmed symptomatic acute PE, identified from the multicenter, international, prospective, Registro Informatizado de la Enfermedad TromboEmb\uf3lica (RIETE registry), we aimed to assess the association between thrombolytic therapy and all-cause mortality during the first 3 months after the diagnosis of a PE. After creating two subgroups, stratified by systolic blood pressure (SBP) (< 100 mm Hg vs. other), we used propensity score-matching for a comparison of patients who received thrombolysis to those who did not in each subgroup. RESULTS: Patients who received thrombolysis were younger, had fewer comorbid diseases and more signs of clinical severity compared with those who did not receive it. In the subgroup with systolic hypotension, analysis of propensity score-matched pairs (n = 94 pairs) showed a non-statistically significant but clinically relevant lower risk of death for thrombolysis compared with no thrombolysis (odds ratio [OR] 0.72; 95% confidence interval [CI], 0.36-1.46; P = 0.37). In the normotensive subgroup, analysis of propensity score-matched pairs (n = 217 pairs) showed a statistically significant and clinically meaningful increased risk of death for thrombolysis compared with no thrombolysis (OR 2.32; 95% CI, 1.15-4.68; P = 0.018). When we imputed data for missing values for echocardiography and troponin tests in the group of normotensive patients, we no longer detected the increased risk of death associated with thrombolytic therapy. CONCLUSIONS: In normotensive patients with acute symptomatic PE, thrombolytic therapy is associated with a higher risk of death than no thrombolytic therapy. In hemodynamically unstable patients, thrombolytic therapy is possibly associated with a lower risk of death than no thrombolytic therapy. However, study design limitations do not imply a causal relationship between thrombolytics and outcome