Does use of long-term aspirin impact outcomes in patients with acute pancreatitis?

INTRODUCTION: Although the effect of rectal indomethacin in post-endoscopic retrograde cholangiopancreatography pancreatitis is well established, the effect of aspirin on acute pancreatitis (AP) is not well studied. We investigate the effect of aspirin on AP. METHODS: We collected data from the National Inpatient Sample database from 2016 to 2020, to identify adult patients with acute pancreatitis. Patients were stratified into 2 groups, based on the presence of aspirin use. The primary outcome was mortality, while other outcomes were sepsis, shock, acute kidney injury (AKI), ICU admission, deep venous thrombosis (DVT), pulmonary embolism (PE), portal vein thrombosis (PVT), pseudocyst and ileus. RESULTS: A total of 2.09 million patients met the inclusion criteria, of which 197 170 (9.41%) had long-term aspirin use. The majority of the patients with aspirin use were aged >65 years, male, White and had Medicare insurance. There was a higher incidence of biliary pancreatitis while rates of alcohol-induced pancreatitis were lower in patients with aspirin use. There was a lower incidence of mortality, sepsis, shock, PE, DVT, PVT and pseudocyst in patients with aspirin use. There was no difference in the incidence of ileus, while the incidence of AKI was higher. After adjusting for confounding factors, patients with aspirin use had a 23.6% lower risk of mortality. DISCUSSION: Our results reveal a significant finding of aspirin's protective effect on AP in the US population. Our study is the largest study revealing an association between aspirin and AP. Further studies assessing the role of aspirin use in AP are warranted.

Risk of Postoperative Thromboembolism in Men Undergoing Urological Prosthetic Surgery: An Assessment of 21,413 Men.

PURPOSE: We assessed venous thromboembolism (VTE) and associated risk factors following artificial urinary sphincter (AUS) and inflatable penile prosthesis (IPP) surgery. MATERIALS AND METHODS: Using IBM® MarketScan, a commercial claims database, patients undergoing AUS and IPP surgery were identified using CPT® and ICD (International Classification of Diseases)-10 procedure codes between 2008 and 2017. ICD-9 and -10 codes were used to identify health care visits associated with lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) within 90 days of surgery. Covariates were assessed using a multivariable model to determine association with outcome of DVT and/or PE. RESULTS: A total of 21,413 men underwent AUS (4,870) or IPP (16,543) surgery between 2008 and 2017 with a median age of 62 years and 68 years, respectively. DVT and PE events following AUS and IPP surgery occurred in 1.54% and 1.04%, respectively. A history of varicose veins (HR 2.76; 95% CI 1.11-6.79), prior history of DVT (HR 13.65; 95% CI 7.4-25.19), or PE (HR 7.65; 95% CI 4.01-14.6) in those undergoing AUS surgery was highly associated with development of postoperative VTE. Likewise, prior history of DVT (HR 12.6; 95% CI 7.99-19.93) and PE (HR 8.9; 95% CI 5.6-14.13) was strongly associated with a VTE event following IPP surgery. CONCLUSIONS: In a large cohort of men undergoing AUS and IPP surgery, 1.54% and 1.04% of men experienced a VTE event within 90 days of surgery, respectively. Prior history of varicose veins, DVT, and PE was associated with an increased likelihood of developing a postoperative DVT or PE.

Comparative Analysis of All-Cause Health Care Resource Utilization and Costs Among Venous Thrombosis Patients Without Cancer Prescribed Apixaban or VKAs in France.

INTRODUCTION: The direct oral anticoagulant (DOAC) apixaban has shown to have non-inferior efficacy and better safety than vitamin K antagonists (VKAs) in patients with venous thromboembolism (VTE). We determined whether healthcare resource use (HCRU) and direct all-cause medical and non-medical costs in patients with VTE in France differed between VKAs and apixaban. METHODS: A retrospective cohort study was conducted using French national health data from January 2013-June 2018 for anticoagulant-naïve adults hospitalized with VTE. All-cause costs and HCRU per patient per month (PPPM) were compared between apixaban and VKA cohorts created by 1:1 propensity score matching. Two-part models with bootstrapping were used to calculate marginal effects for costs and HCRU. RESULTS: The matched VKA and apixaban cohorts each comprised 7503 patients. Compared to VKAs, patients prescribed apixaban had significantly lower (P < 0.0001) mean all-cause costs PPPM for outpatient visits (€438.54 vs. €455.58), overall laboratory tests (€21.26 vs. €83.73), and hospitalizations (€249.48 vs. €343.82), but significantly higher (P < 0.0001) mean all-cause costs PPPM for overall drugs (€97.06 vs. €69.56) and medical procedures (€42.12 vs. €35.50). Mean total all-cause direct medical costs (€687.93 vs. €798.70) and total all-cause direct medical and non-medical costs (€771.60 vs. €883.66) were significantly lower (P < 0.0001) for apixaban. Mean HCRU PPPM showed similar trends. Subgroup analyses showed that, among patients with recurrent VTE, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€17.26 vs. €18.12) and total all-cause direct medical and non-medical costs (€18.37 vs. €19.20) than patients prescribed VKAs. Similarly, among patients with bleeding, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€15.34 vs. €32.61) and total all-cause direct medical and non-medical costs (€16.23 vs. €34.63) than patients prescribed VKAs. CONCLUSION: Compared to VKAs, apixaban may be cost-saving in the treatment of patients hospitalized for acute VTE.

Derivation and Validation of a Risk Assessment Model for Immunomodulatory Drug-Associated Thrombosis Among Patients With Multiple Myeloma.

BACKGROUND: Although venous thromboembolism (VTE) is a significant complication for patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), no validated clinical model predicts VTE in this population. This study aimed to derive and validate a new risk assessment model (RAM) for IMiD-associated VTE. METHODS: Patients with newly diagnosed MM receiving IMiDs were selected from the SEER-Medicare database (n=2,397) to derive a RAM and then data from the Veterans Health Administration database (n=1,251) were used to externally validate the model. A multivariable cause-specific Cox regression model was used for model development. RESULTS: The final RAM, named the "SAVED" score, included 5 clinical variables: prior surgery, Asian race, VTE history, age ≥80 years, and dexamethasone dose. The model stratified approximately 30% of patients in both the derivation and the validation cohorts as high-risk. Hazard ratios (HRs) were 1.85 (P<.01) and 1.98 (P<.01) for high- versus low-risk groups in the derivation and validation cohorts, respectively. In contrast, the method of stratification recommended in the current NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease had HRs of 1.21 (P=.17) and 1.41 (P=.07) for the corresponding risk groups in the 2 datasets. CONCLUSIONS: The SAVED score outperformed the current NCCN Guidelines in risk-stratification of patients with MM receiving IMiD therapy. This clinical model can help inform providers and patients of VTE risk before IMiD initiation and provides a simplified clinical backbone for further prognostic biomarker development in this population.

Hormonal prevention of breast cancer.

Breast cancer prevention can be provided by using SERMs or aromatase inhibitors depending on the ovarian status, with a global risk reduction of 50 to 60%. Prophylactic annexectomy offered to reduce ovarian risk in BRCA mutation carriers also lowers breast cancer risk by 50%. Main side effects include deep vein thrombosis for SERMs, hot flushes and joint pain (although less frequently than initially suspected) with aromatase inhibitors. Other strategies based on progesterone, insulin or prolactin signaling modulation may be offered in the future. Criteria for candidate selection remain to be established.

"Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group.

Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (≥PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease.

Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature.

AIMS: Angiotensin-II receptor 1 antagonists (AT1-antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1-antagonist treatment during the second or third trimester of pregnancy. METHODS: Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1-antagonist fetopathy were: oligo-/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death. RESULTS: In 5/29 (17%) prospectively enrolled cases with AT1-antagonist exposure beyond the first trimester oligo-/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo-/anhydramnios was reversible after AT1-antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive. CONCLUSIONS: Our survey suggests that the risk increases with duration of AT1-antagonist treatment into late pregnancy and oligo-/anhydramnios may be reversible after AT1-antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1-antagonist fetopathy. AT1-antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1-antagonist exposure should be considered.

Inflammation modulates murine venous thrombosis resolution in vivo: assessment by multimodal fluorescence molecular imaging.

OBJECTIVE: Assessment of thrombus inflammation in vivo could provide new insights into deep vein thrombosis (DVT) resolution. Here, we develop and evaluate 2 integrated fluorescence molecular-structural imaging strategies to quantify DVT-related inflammation and architecture and to assess the effect of thrombus inflammation on subsequent DVT resolution in vivo. METHODS AND RESULTS: Murine DVT were created with topical 5% FeCl(3) application to thigh or jugular veins (n=35). On day 3, mice received macrophage and matrix metalloproteinase activity fluorescence imaging agents. On day 4, integrated assessment of DVT inflammation and architecture was performed using confocal fluorescence intravital microscopy. Day 4 analyses showed robust relationships among in vivo thrombus macrophages, matrix metalloproteinase activity, and fluorescein isothiocyanate-dextran deposition (r>0.70; P<0.01). In a serial 2-time point study, mice with DVT underwent intravital microscopy at day 4 and day 6. Analyses revealed that the intensity of thrombus inflammation at day 4 predicted the magnitude of DVT resolution at day 6 (P<0.05). In a second approach, noninvasive fluorescence molecular tomography-computed tomography was used and detected macrophages within jugular DVT (P<0.05 versus sham controls). CONCLUSIONS: Integrated fluorescence molecular-structural imaging demonstrates that the DVT-induced inflammatory response can be readily assessed in vivo and can inform the magnitude of thrombus resolution.

Complications associated with erythropoietin-stimulating agents in patients with metastatic breast cancer: a Surveillance, Epidemiology, and End Results-Medicare study.

BACKGROUND: The authors evaluated the patterns of use and the risk of thromboembolic events (TEE) associated with erythropoietin-stimulating agents (ESAs) in older patients with metastatic breast cancer who were receiving chemotherapy. METHODS: The study was retrospective and used the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995-2005, treated with chemotherapy, ≥66 years old, with full coverage of Medicare A and B were included. The World Health Organization's International Classification of Diseases (ICD-9) and the Healthcare Common Procedure Coding System (HCPCS) were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression. RESULTS: Of 2266 women, 980 (43.3%) received ESAs, and 1286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines, or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, P = .031); deep-vein thrombosis (DVT; 21.3% vs 14.4%, P<.001), other/unspecified thromboembolic event (TEE; 19.8% vs 14.7%, P = .001), and any clot (31.3% vs 23.4%, P<.0001). In multivariate analysis, patients receiving ESAs had increased risk for DVT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.75), and any clot (OR, 1.26; 95% CI, 1.02-1.57). A dose-dependent effect was evident for stroke, DVT, other TEE, and any clot. CONCLUSIONS: In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE, and any clot. The data show that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore, caution is recommended when using these agents.

Costs of managing adverse events in the treatment of first-line metastatic renal cell carcinoma: bevacizumab in combination with interferon-alpha2a compared with sunitinib.

BACKGROUND: Bevacizumab plus interferon-alpha2a (IFN) prolongs progression-free survival to >10 months, which is comparable with sunitinib as first-line treatment of metastatic renal cell carcinoma (RCC). The two regimens have different tolerability profiles; therefore, costs for managing adverse events may be an important factor in selecting therapy. METHODS: Costs of managing adverse events affecting patients with metastatic RCC eligible for treatment with bevacizumab plus IFN or sunitinib were evaluated using a linear decision analytical model. Management costs were calculated from the published incidence of adverse events and health-care costs for treating adverse events in the United Kingdom, Germany, France and Italy. RESULTS: Adverse event management costs were higher for sunitinib than for bevacizumab plus IFN. The average cost per patient for the management of grade 3-4 adverse events was markedly lower with bevacizumab plus IFN compared with sunitinib in the United Kingdom (euro1475 vs euro804), Germany (euro1785 vs euro1367), France (euro2590 vs euro1618) and Italy (euro891 vs euro402). The main cost drivers were lymphopaenia, neutropaenia, thrombocytopaenia, leucopaenia and fatigue/asthaenia for sunitinib; and proteinuria, fatigue/asthaenia, bleeding, anaemia and gastrointestinal perforation for bevacizumab plus IFN. CONCLUSION: The costs of managing adverse events are lower for bevacizumab plus IFN than for sunitinib. The potential for cost savings should be considered when selecting treatments for RCC.

Recombinant activated factor VII use in critically ill infants with active hemorrhage.

INTRODUCTION: Recombinant activated factor VII (rFVIIa) is infrequently used off-label in infants despite a paucity of data in this population. We report a retrospective review of rFVIIa use in infants focusing on safety and efficacy. METHOD: Between 2002 and 2007, 32 critically ill nonhemophiliac infants less than 1 year old received rFVIIa at our institution. Indications of rFVIIa and post-rFVIIa venous thrombosis were reviewed. Transfusion requirements were calculated 8 hours before and after rFVIIa administration. RESULTS: Infants received on average 2 doses of rFVIIa at a mean dosage of 90 microg/kg. Active hemorrhage was the indication for rFVIIa in 24 infants, which included postoperative bleeding in 16 and nonsurgical bleeding in 8. The remaining 8 infants had preoperative coagulopathy. Thrombosis was noted in 4 infants (13%) and was not related to transfusion requirements, the number of doses, or dosage of rFVIIa. For infants who had active hemorrhage, rFVIIa was able to significantly reduce the requirements of packed red blood cells by 36.17 mL/kg (P < .005), platelets by 10.31 mL/kg (P < .01), and cryoprecipitates by 2.19 mL/kg (P < .05). CONCLUSION: This is the first large case series demonstrating the efficacy of rFVIIa in critically ill infants with active hemorrhage by reducing their transfusion requirements. Furthermore, venous thrombosis was not associated with increase in either the number of doses or dosage of rFVIIa.

Aprotinin in pediatric neuromuscular scoliosis surgery.

Reduction of blood transfusions in patients with neuromuscular scoliosis can decrease potential complications such as immune suppression, infection, hemolytic reaction and viral transmission. Aprotinin (Trasylol), Bayer), an antifibrinolytic, has proven to be effective in reducing blood loss in cardiac and liver surgery, but little data exists in patients undergoing spinal fusion for neuromuscular scoliosis. The purpose of this study was to evaluate the safety and efficacy of aprotinin in pediatric neuromuscular scoliosis patients undergoing spinal fusion. The medical records of all patients undergoing initial spinal fusions for neuromuscular scoliosis between January 1999 and March 2003 were reviewed to determine demographic data, perioperative data, wound drainage and number of transfusion required. Cases were compared to a matched group of historical controls. We had 14 patients in the aprotinin group and 17 in the control group. Total blood loss in the aprotinin group was significantly lower compared to the control group (715 vs. 2,110 ml; P = 0.007). Significantly less blood loss occurred in the aprotinin group when blood loss per kilogram was evaluated as well (23 vs. 60 ml/kg, respectively; P = 0.002). Intra-operative packed red blood cell (PRBC) transfusions were also significantly lower in the aprotinin group (1.25 vs. 3.16 units; P = 0.001). No clinical evidence of anaphylaxis, deep vein thrombosis (DVT) or renal failure was observed in the aprotinin group. After considering the price of drug therapy, operating room time, and the cost of blood products, the use of aprotinin saved an average of $8,577 per patient. In our series, the use of aprotinin resulted in decreased blood loss and a decreased rate of transfusions in children with neuromuscular scoliosis undergoing extensive spinal fusion. At out institution, the use of aprotinin is safe and cost effective for patients with neuromuscular scoliosis.

Safety assessment of raloxifene over eight years in a clinical trial setting.

OBJECTIVE: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting. METHODS: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4-year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4-year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test. RESULTS: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups (p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively (p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93-3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups (p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo (p = 0.028, p < 0.001, and p = 0.008, respectively). CONCLUSION: These 8-year data support the known clinical safety profile of raloxifene, established in the MORE trial.

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Deep vein thrombosis and pulmonary embolism reported in the Prescription Event Monitoring Study of Yasmin.

AIM: To evaluate cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) reported in a prescription event monitoring study of Yasmin, an oral contraceptive. METHODS: Reports of DVT/PE and events suggestive of DVT/PE were followed up by questionnaire. RESULTS: Thirteen cases (DVT five; PE eight), each with possible risk factor(s), were identified in 15 645 females using Yasmin. Applying complete case analysis, the crude incidence rate was 13.7 cases per 10 000 woman-years (95% confidence interval 7.3, 23.4). CONCLUSIONS: Yasmin is associated with venous thromboembolism. An incidence rate has been calculated, but this may be subject to bias and should be interpreted with caution.