Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi therapeutic in infants and young children.

PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS: All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Population-Based Pharmacokinetic and Exposure-Efficacy Analyses of Peginterferon Beta-1a in Patients With Relapsing Multiple Sclerosis.

Peginterferon beta-1a reduced annualized relapse rate as compared with placebo and was approved to treat multiple sclerosis patients. A population pharmacokinetic and an exposure-efficacy model were developed to establish the quantitative relationship between pharmacokinetics and annualized relapse rate. The pharmacokinetics was well described by a 1-compartment model with first-order absorption and linear elimination kinetics. Body mass index was the most significant covariate that impacted both clearance and volume of distribution, which in turn impacted area under the curve and maximum serum concentration. Cumulative monthly area under the curve and annualized relapse rate were best described by a Poisson-gamma (negative binomial) model, demonstrating that the improved efficacy of every-2-weeks dosing was driven by greater drug exposure. The results supported the superior efficacy of the every-2-week dosing regimen compared with the every-4-weeks dosing regimen.

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

BACKGROUND: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. OBJECTIVE: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. METHODS: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 µg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. RESULTS: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. CONCLUSION: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.

COMPARE: Pharmacokinetic profiles of subcutaneous peginterferon beta-1a and subcutaneous interferon beta-1a over 2 weeks in healthy subjects.

AIM: Subcutaneous (s.c.) peginterferon beta-1a injected once every 2 weeks and s.c. interferon beta-1a injected three times per week (Rebif®) have demonstrated efficacy in relapsing-remitting multiple sclerosis, but direct comparisons of pharmacological activity and tolerability between the two products are lacking. COMPARE was an open label, crossover, pharmacokinetic (PK) study evaluating drug exposure and the safety and tolerability of s.c. peginterferon beta-1a and s.c. interferon beta-1a, over 2 weeks in healthy subjects. METHODS: Thirty healthy subjects received one dose of peginterferon beta-1a (125 µg s.c.) or six doses of interferon beta-1a (44 µg s.c.) over 2 weeks, followed by the alternate treatment after a 2 week washout period. Drug concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and PK parameters including cumulative area under the concentration-time curve (AUC0-336h ) over 2 weeks and maximum observed serum concentrations (Cmax ) were estimated using a non-compartmental analysis. RESULTS: The PK analysis population comprised 26 subjects for each treatment. Drug exposure (AUC0-336h ) was 60% higher with s.c. peginterferon than with s.c. interferon beta-1a (117.4 ng ml(-1) h, 95% confidence interval 95.6, 144.3 vs. 73.1 ng ml(-1) h, 95% confidence interval 61.2, 87.3, respectively; P < 0.0001). Injection-site reactions (ISRs) were the most common adverse events (AEs) observed with both treatments. Numerically lower frequencies and incidence rates of ISRs, headache, myalgia and chills were observed with s.c. peginterferon beta-1a. CONCLUSIONS: One dose of s.c. peginterferon delivered significantly greater drug exposure than s.c. interferon beta-1a three times a week over 2 weeks, and a lower frequency of AEs.

Pharmacokinetics, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function.

Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 µg (n = 5) or 125 µg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.

Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE.

OBJECTIVE: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study. METHODS: Patients were randomized to placebo or 125 µg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. RESULTS: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. CONCLUSIONS: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1.Clinicaltrials.gov REGISTRATION NUMBER: NCT00906399.

Single-use autoinjector for peginterferon-ß1a treatment of relapsing-remitting multiple sclerosis: safety, tolerability and patient evaluation data from the Phase IIIb ATTAIN study.

OBJECTIVES: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-ß1a (a pegylated interferon-ß1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study. METHODS: Over 8 weeks, patients self-administered peginterferon-ß1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials. RESULTS: In 39 patients, the safety profile of peginterferon-ß1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high. CONCLUSION: The safety and tolerability profile of peginterferon-ß1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient's quality of life and adherence.

Pegylated interferon ß-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study.

BACKGROUND: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis. METHODS: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 µg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399. FINDINGS: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common. INTERPRETATION: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments. FUNDING: Biogen Idec.

Strains of Ehrlichia chaffeensis in southern Indiana, Kentucky, Mississippi, and North Carolina.

Rates of infection of Amblyomma americanum (L.) by Ehrlichia chaffeensis were compared in 100 ticks collected from sites in each of four states: Indiana, North Carolina, Kentucky, and Mississippi. The overall infection rates were similar among sites, ranging from 1 to 4%. Because pathogenic differences may exist between E. chaffeensis strains, nested polymerase chain reaction (PCR) amplification of the variable-length PCR target (VLPT), and sequencing of the amplicons were performed to differentiate between strains. The most common infecting strains at all sites exhibited a repeat profile of 1,2,3,4 (corresponding to the Arkansas/Jax/Osceola and Liberty strains). To determine whether the minimum infection rates (MIRs) or the most common infecting strain were changing over time in southern Indiana sites, 2765 ticks from six counties in 2000 and 837 ticks from seven counties in 2004 also were examined in pools of five ticks per pool. The MIRs for 2000 and 2004 were 3.5 and 4.2% respectively, suggesting that the overall MIRs remained low. At two sites, in Pike and Harrison counties, however, infection rates more than doubled from 2000 to 2004 (7 to 16% and 0.3 to 2.7% respectively). Across all sites, the most common infecting strains (Arkansas/Jax/Osceola and Liberty) did not significantly change (68% in 2000; 79% in 2004).

Deep vein thrombosis in orthopedic surgery.

We compared 315 patients with deep vein thrombosis who underwent major orthopedic surgery with 618 who underwent general surgery in a prospective registry of consecutive ultrasound-confirmed deep vein thrombosis patients. Orthopedic patients had fewer indwelling central venous catheters (14.0% vs. 46.4%, P < .0001) as well as lower rates of congestive heart failure (7.0% vs. 13.4%, P = .002), cancer (5.1% vs. 28.6%, P < .0001), and diabetes (7.0% vs. 12.6%, P = .004). Extremity discomfort (43.5% vs. 30.3%, P < .0001) and erythema (10.1% vs. 4.8%, P = .001) were more common in orthopedic patients, but dyspnea was less common (11.4% vs. 18.0%, P = .005). There was an increased use of graduated compression stockings (19.4% vs. 15.0%, P = .04), low-molecular-weight heparin (18.7% vs. 12.1%, P = .003), and warfarin (31.7% vs. 11.0%, P < .0001) for deep vein thrombosis prophylaxis in the orthopedic surgery group. Orthopedic surgical patients had a higher frequency of calf deep vein thrombosis than patients who underwent general surgery (38.4% vs. 2.1%, P < .0001). In both groups, 28% did not receive prophylaxis. In conclusion, despite having fewer comorbid conditions, orthopedic patients with deep vein thrombosis remain particularly vulnerable to calf deep vein thrombosis. Rates of venous thromboembolism prophylaxis were inadequate.

Gastrointestinal complications after 3 months of dual antiplatelet therapy for drug-eluting stents as assessed by wireless capsule endoscopy.

Little is known about the frequency of symptomatic and asymptomatic gastrointestinal complications of dual antiplatelet therapy. We recruited 30 patients between 18 and 80 years who were started on aspirin and clopidogrel following percutaneous coronary intervention with drug-eluting stents. We hypothesized that the 3 months of dual antiplatelet therapy would be associated with frequent upper gastrointestinal endoscopic abnormalities. Patients were followed with weekly phone calls to inquire about the new gastrointestinal symptoms and after a minimum of 80 days, their upper gastrointestinal mucosa was visualized with PillCam ESO wireless capsule endoscopy. 18 (90%) of the 20 successful wireless capsule endoscopies revealed at least 1 type of gastrointestinal mucosal lesion. Gastric erosions (n = 14, 70%) were the most common abnormality. We believe this is the first noninvasive endoscopic study of gastrointestinal complications of dual antiplatelet therapy in patients who undergo percutaneous coronary intervention with drug-eluting stents. Future studies should expand on our observations to determine whether prophylaxis with proton pump inhibitors is warranted.

Deep-vein thrombosis in the elderly.

Venous thromboembolism, including deep-vein thrombosis and pulmonary embolism, is a major source of morbidity and mortality among elderly patients. To improve our understanding of elderly patients with deep-vein thrombosis, we compared 1932 patients with deep-vein thrombosis aged 70 years or older with 2554 nonelderly patients in a prospective registry of consecutive ultrasound-confirmed deep-vein thrombosis patients. The mean age of elderly patients was 78.9 +/- 6.1 years compared with 51.8 +/- 12.9 years in nonelderly (P < .0001). Elderly patients were more likely to have prior recent hospitalization (49.2% vs 44.7%, P = .03), congestive heart failure (20.5% vs 9.9%, P < .0001), chronic obstructive pulmonary disease (18.2% vs 11.7%, P < .0001), and recent immobilization (50.5% vs 39.6%, P < .0001) than the nonelderly patients. Elderly patients were less likely to present with typical deep-vein thrombosis symptoms of extremity discomfort (44.4% vs 60.6%, P < .0001) and difficulty ambulating (8.4% vs 11.2%, P = .002). Only 41% of elderly patients subsequently diagnosed with deep-vein thrombosis had received any venous thromboembolism prophylaxis. In conclusion, elderly patients with deep-vein thrombosis represent a particularly vulnerable population with numerous comorbid conditions. Diagnosis can present a challenge because typical deep-vein thrombosis symptoms may be absent. Fewer than 50% of elderly patients with deep-vein thrombosis had received any venous thromboembolism prophylaxis.

Deep vein thrombosis in patients with chronic kidney disease.

Deep vein thrombosis (DVT) is a poorly understood complication of chronic kidney disease (CKD). The objective of our analysis was to profile DVT patients with and without CKD. We defined CKD as patients requiring dialysis or patients having nephrotic syndrome. We compared 268 patients with CKD (184 patients with dialysis-dependent renal disease and 84 with nephrotic syndrome) to 4,307 patients with preserved renal function from a prospective United States multicenter deep venous thrombosis (DVT) registry. Compared with non-CKD patients, CKD patients with DVT were younger (median age 62 vs. 69 years, p < 0.0001), more often African-American (p < 0.0001), and more often Hispanic (p = 0.0003). CKD patients underwent surgery more frequently in the three months prior to developing DVT (48.9% vs. 39.0%, p = 0.001) and more often had concomitant congestive heart failure (20.9% vs. 14.6%, p = 0.005). CKD patients suffered upper extremity DVT more frequently (30.0% vs. 10.8%, p < 0.0001). Patients with CKD presented less often with typical DVT symptoms of extremity discomfort (42.9% vs. 52.4%, p = 0.003) and difficulty ambulating (5.4% vs. 10.1%, p = 0.01). Prophylaxis rates prior to DVT were similarly low in CKD and non-CKD patients (44.2% vs. 38.0%, p = 0.06). Future studies of DVT in CKD patients should explore novel strategies for improving prophylaxis utilization and the detection of DVT in this special population.

Heart failure in patients with deep vein thrombosis.

Patients with heart failure (HF) are particularly vulnerable to the development of venous thromboembolism (VTE) and its related complications of pulmonary embolism and right ventricular failure. To improve our understanding of the clinical characteristics, prophylaxis, and initial management of patients with HF and deep vein thrombosis (DVT), we compared 685 patients with a history of HF with 3,890 patients without HF in a prospective registry of 5,451 consecutive patients with ultrasound-confirmed DVT. We excluded 876 patients for whom data regarding HF status were incomplete. Patients with HF had an increased frequency of co-morbid conditions such as neurologic disease including stroke (33% vs 26%, p = 0.0002), acute lung disease including pneumonia (31% vs 15%, p <0.0001), and acute coronary syndrome (11% vs 4%, p <0.0001) contributing to a higher medical acuity than in patients without HF. Furthermore, patients with HF were more likely to have VTE risk factors of immobilization (53% vs 42%, p <0.0001), acute infection (33% vs 27%, p = 0.01), and chronic obstructive pulmonary disease (29% vs 12%, p <0.0001). Patients with and without HF and DVT had a high frequency of recent hospitalization (48% vs 47%, p = 0.96). Fewer than 12 of patients with HF (46%) who subsequently developed DVT received any VTE prophylaxis. In conclusion, the combination of higher medical acuity, increased frequency of VTE risk factors, and low rate of VTE prophylaxis presents a "triple threat" to patients with HF.

Chronic obstructive pulmonary disease and deep vein thrombosis: a prevalent combination.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for venous thromboembolism (VTE). We analyzed a large US deep vein thrombosis (DVT) registry to explore the profile of patients with COPD and VTE. METHODS: Demographics, symptoms, risk factors, prophylaxis, and initial management of 668 (12%) patients with COPD were compared to 3,907 patients without COPD from a prospective registry of 5,451 consecutive patients with ultrasound-confirmed DVT at 183 institutions in the United States. RESULTS: COPD patients with DVT were older (median 72.5 years vs. 68.0 years, P < 0.0001) and more likely to be male (52.3% vs. 44.8%, P = 0.0004). They were more likely to be inpatients at the time of diagnosis of DVT (62.0% vs. 51.9%, P < 0.0001). COPD patients were more likely to be admitted to the intensive care unit (ICU) (27.7% vs.19.8%, P = 0.0003), more likely to require mechanical ventilation (23.2% vs. 13.6%, P < 0.0001), and more likely to receive inferior vena caval (IVC) filters (19.1% vs. 15.1%, P = 0.009). COPD patients more often had concomitant pulmonary embolism (PE) (22.8% vs.17.8%, P = 0.005) as well as concomitant congestive heart failure (29.5% vs. 12.5%, P < 0.0001). CONCLUSIONS: DVT patients with COPD have a greater medical acuity than other DVT patients. This results in more frequent IVC filter insertion.

Venous thromboembolism in patients undergoing surgery: low rates of prophylaxis and high rates of filter insertion.

Patients who undergo surgery are at a high risk of developing venous thromboembolism (VTE). To further define the demographics, comorbidities, and risk factors of VTE in patients undergoing major surgery, we analyzed 1,375 hospitalized non-orthopedic surgery patients in a prospective registry of 5,451 patients with ultrasound confirmed deep vein thrombosis (DVT) from 183 hospitals in the United States. Extremity edema (67.9%), extremity discomfort (44.9%), and dyspnea (18.9%) were among the most common presenting symptoms among these surgical patients. Compared to medical patients, surgical patients presented with a more occult clinical picture and complained less often of extremity edema (67.9% vs. 73.7%; p = 0.0001), extremity discomfort (44.9% vs. 56.4%; p < 0.0001), or difficulty walking (6.6% vs. 11.2%; p < 0.0001). Immobility within 30 days of DVT diagnosis, prior hospitalization within 30 days of DVT diagnosis, presence of an indwelling central venous catheter, obesity (BMI>30 kg/m2), and previous smoking were the most commonVTE risk factors among surgical patients. Among surgical patients who developed DVT, some form of prophylaxis had been used in only 44%. Once diagnosed with DVT, surgical patients received IVC filters more often than medical patients (20.0% vs. 14.1%; p < 0.0001; adjusted OR = 1.49, 95% CI = 1.17-1.92; p < 0.001). In conclusion, VTE prophylaxis remains underutilized in surgical patients. The IVC filter utilization rate in surgical patients is significantly higher than in medical patients. Future studies should focus on devising mechanisms to improve implementation of prophylaxis and investigate the long-term safety and efficacy of IVC filters in surgical patients.

Venous thromboembolism in patients with active cancer.

Patients with cancer have an increased risk of venous thromboembolism (VTE). To further define the demographics, comorbidities, and risk factors of VTE in these patients, we analyzed a prospective registry of 5,451 patients with ultrasound confirmed deep vein thrombosis (DVT) from 183 hospitals in the United States. Cancer was reported in 1,768 (39%), of whom 1,096 (62.0%) had active cancer. Of these, 599 (54.7%) were receiving chemotherapy, and 226 (20.6%) had metastases. Lung (18.5%), colorectal (11.8%), and breast cancer (9.0%) were among the most common cancer types. Cancer patients were younger (median age 66 years vs. 70 years; p < 0.0001), were more likely to be male (50.4% vs. 44.5%; p = 0.0005), and had a lower average body mass index (26.6 kg/m(2) vs. 28.9 kg/m(2); p < 0.0001). Cancer patients less often received VTE prophylaxis prior to development of DVT compared to those with no cancer (308 of 1,096, 28.2% vs. 1,196 of 3,444, 34.6%; p < 0.0001). For DVT therapy, low-molecular-weight heparin (LMWH) as monotherapy without warfarin (142 of 1,086, 13.1% vs. 300 of 3,429, 8.7%; p < 0.0001) and inferior vena caval filters (234 of 1,086, 21.5% vs. 473 of 3,429, 13.8%; p < 0.0001) were utilized more often in cancer patients than in DVT patients without cancer. Cancer patients with DVT and neurological disease were twice as likely to receive inferior vena caval filters than those with no cancer (odds ratio 2.17, p = 0.005). In conclusion, cancer patients who develop DVT receive prophylaxis less often and more often receive filters than patients with no cancer who develop DVT. Future studies should focus on ways to improve implementation of prophylaxis in cancer patients and to further define the indications, efficacy, and safety of inferior vena caval filters in this population.

Double trouble for 2,609 hospitalized medical patients who developed deep vein thrombosis: prophylaxis omitted more often and pulmonary embolism more frequent.

BACKGROUND: Hospitalized patients with medical illness are especially susceptible to the development of venous thromboembolism (VTE). METHODS: To improve our understanding of the demographics, comorbidities, risk factors, clinical presentation, prophylaxis, and treatment of hospitalized medical patients with deep vein thrombosis (DVT), we evaluated hospitalized medical patients in a prospective registry of 5,451 consecutive ultrasound-confirmed DVT patients at 183 institutions in the United States. RESULTS: Of those patients who participated in the registry, 2,609 (48%) were hospitalized medical patients. Compared with 1,953 hospitalized nonmedical patients with DVT, medical patients with DVT experienced pulmonary embolism (PE) more often (22.2% vs 15.5%, respectively; p < 0.0001). However, medical patients in whom DVT developed had received VTE prophylaxis far less frequently than nonmedical patients (25.4% vs 53.8%, respectively; p < 0.0001). The underutilization of VTE prophylaxis among hospitalized medical patients extended to both pharmacologic and mechanical modalities. In a multivariable logistic regression analysis of all hospitalized VTE patients, status as a medical patient was negatively associated with receiving prophylaxis (adjusted odds ratio, 0.47; 95% confidence interval, 0.28 to 0.78). CONCLUSIONS: Hospitalized medical patients face "double trouble." First, during hospitalization for a reason other than VTE, VTE prophylaxis is omitted in medical patients more often than in nonmedical patients. Second, when VTE develops as a complication of hospitalization, hospitalized medical patients experience PE more often. Further studies should focus on understanding why prophylaxis is often omitted in hospitalized medical patients and on improving its implementation in this vulnerable population.