Off-label Group Research Articles

Off‐label intravenous thrombolysis in acute stroke

Therapy for stroke with intravenous tissue plasminogen activator (IV-tPA) is hampered by tight licensing restrictions; some of them have been discussed in recent literature. We assessed the safety and effectiveness of off-label IV-tPA in the clinical settings. Retrospective analysis of all the patients treated with IV-tPA at our Stroke Unit. Patients were divided into two groups by licence criteria [on-label group (OnLG), off-label group (OffLG)]. Primary outcome measures were symptomatic intracranial haemorrhages (sICH), major systemic haemorrhages, modified Rankin scale (mRS) and mortality rate at 3months. Five hundred and five patients were registered, 269 (53.2%) were assigned to OnLG and 236 (46.9%) to OffLG. Inclusion criteria for the OffLG were aged >80 years (129 patients), time from onset of symptoms to treatment over 3h (111), prior oral anticoagulant treatment with International Normalised Ratio≤1.7 (41), combination of previous stroke and diabetes mellitus (14), surgery or severe trauma within 3months of stroke (13), National Institutes of Health Stroke Scale score over 25 (11), intracranial tumours (5), systemic diseases with risk of bleeding (7) and seizure at the onset of stroke (2). No significant differences were identified between both groups regarding the proportion of sICH (OnLG 2.2% vs. OffLG 1.6%, P=0.78) or the 3-month mortality rate (11.1% vs. 19%: odds ratio (OR), 1.49; 95% CI, 0.86-2.55; P=0.14). Multivariate analysis showed no significant differences in functional independence at 3months between both groups (mRS <3 64.3% vs. 50.4%: OR mRS >2 1.7; 95% CI, 0.96-2.5; P=0.07). Intravenous thrombolysis may be safe and efficacious beyond its current label restrictions.

Complications associated with off-label use of recombinant factor VIIa

A retrospective multi-center cohort study of the off-label use of recombinant factor VIIa in tertiary care pediatric hospitals across the United States was completed by Witmer et al from the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine. Studying children 18 years of age or younger who received this therapy between 2000 and 2007, the authors identified 4942 eligible admissions, of which 74% represented off-label use of the factor. They demonstrated a ten-fold increase in the annual rate of off-label admissions during this time period, in spite of an absence of adequate clinical trials demonstrating safety and efficacy. This is of concern because the mortality rate in the off-label group was 34%, and thrombotic events occurred in 11% in the off-label admissions. Given these high rates of thrombosis and mortality in patients receiving off-label recombinant factor VIIa, further studies are needed to determine the causes of these adverse events and the safety of this therapy.Article page 820▶ A retrospective multi-center cohort study of the off-label use of recombinant factor VIIa in tertiary care pediatric hospitals across the United States was completed by Witmer et al from the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine. Studying children 18 years of age or younger who received this therapy between 2000 and 2007, the authors identified 4942 eligible admissions, of which 74% represented off-label use of the factor. They demonstrated a ten-fold increase in the annual rate of off-label admissions during this time period, in spite of an absence of adequate clinical trials demonstrating safety and efficacy. This is of concern because the mortality rate in the off-label group was 34%, and thrombotic events occurred in 11% in the off-label admissions. Given these high rates of thrombosis and mortality in patients receiving off-label recombinant factor VIIa, further studies are needed to determine the causes of these adverse events and the safety of this therapy. Article page 820▶ Off-Label Recombinant Factor VIIa Use and Thrombosis in Children: A Multi-Center Cohort StudyThe Journal of PediatricsVol. 158Issue 5PreviewTo describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. Full-Text PDF

Comparison between on-label versus off-label use of drug-eluting coronary stents in clinical practice: results from the German DES.DE-Registry

Observational studies from the USA have demonstrated that off-label use of drug-eluting stents (DES) is common. Data on off-label use in Western Europe are limited. We analyzed the data of consecutive patients receiving DES prospectively enrolled in the multicenter German DES.DE registry (Deutsches Drug-Eluting Stent Register) between October 2005 and October 2006. Off-label use was defined in the presence of one of the following criteria: ST-elevation myocardial infarction, in-stent stenosis, chronic total occlusion, lesions in a bypass graft, in bifurcation or left main stem, stent length per lesion≥32mm, and vessel diameter<2.5 or>3.5mm. Overall, 4,295 patients were included in this analysis and divided into two groups: 2,366 (55.1%) received DES for off-label and 1,929 (44.9%) for on-label indications. There were substantial differences in the rates of off-label use at the participating hospitals. Patients with off-label DES more often presented with high-risk features such as acute coronary syndrome, cardiogenic shock, congestive heart failure, and more complex coronary anatomy. Among hospital survivors, the incidence of the composite endpoint of death, myocardial infarction and stroke (MACCE) (9.2 vs. 7.4%, p<0.05), and target vessel revascularization (TVR) (11.3 vs. 9.1%, p<0.05) was increased in the off-label group at the 1-year follow-up. However, in the multivariate analysis off-label use was not linked with an elevated risk for MACCE (hazard ratio 0.86, 95% confidence interval 0.62-1.18) and TVR (hazard ratio 1.05, 95% confidence interval 0.78-1.42). In clinical practice, DES was very frequently used off-label. After adjustment for confounding variables, off-label use was not associated with an increase of adverse events.

Evaluation of the Endurant stent graft under instructions for use vs off-label conditions for endovascular aortic aneurysm repair

This study evaluated the early and intermediate results of endovascular aortic aneurysm repair (EVAR) using the Endurant stent graft (Medtronic Cardiovascular, Santa Rosa, Calif) in patients treated according to device-specific instructions for use (IFU) for the proximal aortic neck compared with those obtained in patients treated in an off-label (OL) situation. Between November 2007 and March 2010, 177 consecutive patients with abdominal aortic aneurysms (AAAs) were treated with the Endurant stent graft at our centers. The IFU for the Endurant stent graft included a proximal neck of 15 mm in length and <75° of angulation or 10 mm of neck length and <60° of angulation. The 121 patients (68.4%) operated on according to IFU were compared with 56 (31.6%) who underwent EVAR in OL circumstances to evaluate significant differences in demographics, intraoperative technical factors, and early (30 days) and intermediate outcomes (1 year). Significantly more patients were aged >80 years in the OL group (37.5% vs 19%, P = .008), and they also had larger aneurysms (59 ± 10.6 vs 55.9 ± 10.8 mm, P = .05) and required a longer procedure time (69.3 ± 27.2 vs 60.8 ± 20.4 minutes, P = .02). At 30 days, the risk of type I endoleak was higher in the OL group (2 patients, 3.6% vs 0 in IFU), but this did not reach statistical significance (P = .09). The two groups were similar in rates of perioperative mortality, major morbidity, technical success, clinical success, complications, and reinterventions. At 1 year, there were no differences between the two groups in survival, freedom from any device-related reinterventions, and freedom from graft thrombosis. Estimated 1-year freedom from type I endoleak was 100% in the IFU group vs 93.3% in the OL group (P = .01). In patients with both normal and complex anatomy of the proximal aortic neck, the Endurant stent graft obtained acceptable results, with no difference in survival, morbidity, or reinterventions. However, there was a greater risk of type I endoleak when OL indications were applied. Longer term follow-up is required to evaluate the effectiveness of this endograft in preventing late aneurysm-related complications.

Off-Label Recombinant Factor VIIa Use and Thrombosis in Children: A Multi-Center Cohort Study

To describe the off-label use of recombinant factor VIIa (rFVIIa) in tertiary care pediatric hospitals across the United States and to assess thrombotic events. A retrospective multi-center cohort study using the Pediatric Health Information System administrative database. Children 18 years of age or younger who received rFVIIa between 2000 and 2007 were included. A label admission was defined as an admission with an International Classification of Diseases diagnostic code for hemophilia or factor VII deficiency; admissions without these codes were classified as off-label. There were 4942 rFVIIa admissions, representing 3764 individual subjects; 74% (3655) of the admissions were off-label. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10 000 hospital admissions, P < .001). The mortality rate in the off-label group was 34% (1258/3655). Thrombotic events occurred in 10.9% (399/3655) of the off-label admissions. The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. Thrombotic events are common and mortality is high among patients receiving off-label rFVIIa. Further studies are warranted to determine whether these adverse events are attributable to rFVIIa.

Off-Label Recombinant Factor VIIa Use in Pediatrics: a Multicenter Cohort Study.

Abstract 543 Objective:Recombinant factor VIIa (rFVIIa) is an analogue of the naturally occurring procoagulant and has a narrow indication for usage including patients with hemophilia and an inhibitor or factor VII deficiency. In adults, off-label indications account for most rFVIIa usage despite inadequate studies demonstrating safety, dosing and efficacy. Significant concerns exist regarding the thrombotic potential of rFVIIa and the associated morbidity and mortality. The objective of this study was to describe the use of rFVIIa in hospitalized pediatric patients and to assess thrombotic outcomes. Patients and Methods:This retrospective multicenter cohort study used data from 40 free-standing children's hospitals that contribute data to the Pediatric Health Information System administrative database. Children less 18 years of age who received rFVIIa, as determined through pharmacy billing data, between 2000-2007 were included. A label admission was identified when there was an International Classification of Diseases (ICD-9) diagnostic code for hemophilia or Factor VII deficiency; admissions without these codes were classified as off-label. ICD-9 discharge codes were used to identify admissions during which an arterial or venous thromboembolism was diagnosed. Continuous data were analyzed with the student t-test and categorical data with the chi squared test. Poisson regression was used to analyze the rate of rFVIIa use over time. Results:There were a total of 4,942 admissions in which rFVIIa was used, representing 3,764 individual subjects. rFVIIa was used off-label in 74% (3655) of the admissions. There was a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007 (from 2 to 20.8 per 10,000 hospital admissions, p<.0001) (figure 1). Forty percent (1455/3655) of the off-label rFVIIa use occurred in children less than one year of age. The most frequent attending physician specialties for the off-label admissions included hematology/oncology 16.8%, critical care 16.1%, cardiology 10.3%, cardiovascular/thoracic surgery 10.2%, and neonatology 7.4%. In most admissions (88%), the ICD-9 discharge codes included one or more complex chronic conditions (CCC); the most common CCCs were cardiovascular (30%), hemophilia (24%), and malignancy (14%). The mean length of stay was 35.5 +/- 47 days for the off-label admissions. The off-label admissions had a lower mean of the total days of rFVIIa use, 2.3 +/- 4.7, compared to label admissions with 5.1 +/- 5.5 days (p<.001). The mortality rate in the off-label group was 34% (1258/3655) versus 1.6% (21/1287) in the label group (p<.001). Thrombotic events, the majority of which were venous, occurred in 7.7% (283/3655) of the off-label admissions and in 2.3% (30/1287) of the label admissions. [Display omitted] Conclusion:The off-label use of rFVIIa in hospitalized children is increasing rapidly despite the absence of adequate clinical trials demonstrating safety and efficacy. The mortality rate in patients who receive off-label rFVIIa is extremely high, and the proportion of patients who develop a thrombosis is not trivial. Further prospective studies are urgently needed to address the safety and efficacy of this drug. Disclosures:Off Label Use: This paper will report on the off-label use of rFVIIa in pediatric patients.

Adherence to patient selection criteria in patients undergoing transcatheter aortic valve implantation with the 18F CoreValve ReValving System

Background:Anecdotal evidence suggests that transcatheter aortic valve implantation (TAVI) is being used beyond pre-market label indications.Methods:To assess the frequency and outcomes associated with “off-label” use of TAVI, we conducted a...

Off Label Indication of Drugs Eluting Stent: National Cardiovascular Center Harapan Kita’s Experiences

Background. Food and Drug Administration (FDA) of Unites States set the indication of drug-eluting stent (DES) on the product label (on-label indication). In the clinical practice, many patients received DES implantation outside the indication (off-label indication). Several “real-world” register showed off-label implantation reach prevalence of 50-60% with wide-ranging clinical outcomes. Objectives. To report the frequency, procedural complications, stent thrombosis (ST) and major cardiovascular events (MACE) of DES implantation with off-label indication in the National Cardiac Center Harapan Kita. Methods. This retrospective cohort study included patients who underwent coronary intervention with one or more DES (sirolimus or paclitaxel) implantation at 2006. Subjects were grouped into on-label and off-label indication. Subjects were followed-up until mid 2008. Results. 196(59%) of total patients who received DES implantation in 2006 in PJNHK are on off-label indications. The most frequent off-label indication was long-lesion intervention. There were more patients with previous myocardial infarction, PCI and CABG in off-label group. No significant difference of procedural complication rates between on-label and off-label group (2.2% vs. 2.6%, P =0.57). There was no significant difference of stent thrombosis rate. There was higher incident of MACE in off-label than on-label group (17.9% vs. 8.6%, P =0.03). This difference was most contributed by incident of cardiac death. The adjusted hazard ratio of off-label was 1.7 (95% CI 0.8 – 3.6; P = 0.16); with several confounding factors including previous cerebrovascular disease, creatinine clearance <60 mL/min, non-elective PCI and double antiplatelet cessation. Conclusion. Off-label indication was quite frequent but has non-significant difference of TVR and ST rate compared to on-label indication. There was higher incident of MACE in off-label group, but this may be influenced by several clinical confounders

Abstract 3137: Long-term Outcomes Following Sirolimus-Eluting Stent Implantation for Off Label Indications

Introduction: Only limited long term data exist following SES implantation and these primarily come from the randomized trials which enrolled highly selected patients. Due to the risk of stent thrombosis long term safety concerns exist particularly following off label SES implantation. Hypothesis: Off label implantation of SES has a favorable long term safety profile. Methods: All consecutive patients successfully treated with SES prior to March 2003 were considered for analysis. The endpoints analyzed were MACE, death, myocardial infarction (MI), target vessel revascularization (TVR) and target lesion revascularization (TLR) and late stent thrombosis. We considered the following as off-label indications: ostial lesions, chronic total occlusions, bifurcations, left main stem lesions, saphenous vein grafts, internal mammary artery, ejection fraction &lt; 30 %, restenotic lesions. Results: Our cohort comprised 445 patients with 954 lesions. At least one off label indication was present in 322 (72%) of patients and 161 (36.2%) had more than 1 off label indication (Table ). Median clinical follow-up was 4.4 years and 78% of patients had at least 4 years of follow-up. There was a trend towards a higher MACE rate in the off-label group due in the main to a significantly higher repeat revascularization rate. There were no differences in the incidence of death or myocardial infarction. The overall rate of late thrombosis was similar to that seen in the literature (1–2%) and while there was a slightly higher number in the off-label group this did not reach statistical significance. Conclusions: In our experience off label implantation of SES is associated with higher MACE rates due to the increased need for repeat revascularization. This can be explained by the complexity of this cohort with a large number of lesion types not included in randomized trials. Of note long term safety is acceptable with no difference in death or MI when compared to on-label indications. Follow-up clinical events in the two groups

Clinical Outcomes and Stent Thrombosis Following Off-Label Use of Drug-Eluting Stents

Clinical trials that have excluded patients at high risk for cardiac events have led to commercial labeling approval of drug-eluting stents; nevertheless, such high-risk patients commonly undergo stent placement in clinical practice. The degree to which they experience cardiac events at a higher rate than non-high-risk patients is unclear. To assess the rates of major adverse cardiac events during the index admission and 1 year after the implantation of drug-eluting stents in patients with high-risk angiographic and clinical features. From July 2004 to September 2005, consecutive patients who underwent attempted stent placement at 42 different hospitals throughout the United States were enrolled in a prospective multicenter registry. We analyzed outcomes of 3323 patients who received at least 1 drug-eluting stent for a reason other than acute ST-segment elevation myocardial infarction. The study population was divided into 2 groups based on presence of at least 1 of 9 off-label characteristics based on the current US Food and Drug Administration-approved indications for sirolimus- and paclitaxel-eluting stents. The composite clinical outcomes of death, myocardial infarction, or target vessel revascularization during the index admission and death, myocardial infarction, or target lesion revascularization at 1 year were evaluated. Of the 3323 patients, 1817 (54.7%) had at least 1 off-label characteristic. During the index hospitalization, the composite clinical outcome occurred in 198 (10.9%) of patients in the off-label group and 76 (5.0%) of patients in the on-label group (adjusted odds ratio, 2.32; 95% confidence interval [CI], 1.75-3.07; P<.001). At 1 year, the composite clinical outcome occurred more often in the off-label group compared with the on-label group; 309 (17.5%) vs 131 (8.9%) (adjusted hazard ratio [HR], 2.16; 95% CI, 1.74-2.67; P<.001). Stent thrombosis also occurred more frequently among patients in the off-label group during the initial hospitalization (8 [0.4%] vs 0) and at 1 year: 29 (1.6%) vs 13 (0.9%), adjusted HR, 2.29 (95% CI, 1.02-5.16; P = .05). Compared with on-label use, off-label use of drug-eluting stents is associated with a higher rate of adverse outcomes during the index admission and at 1 year. Stent thrombosis occurred predominantly in patients who underwent off-label drug-eluting stent implantation. Clinicians should be cautious about extrapolating the benefits of drug-eluting stents over bare-metal stents observed in randomized clinical trials to higher-risk clinical settings that have not been assessed.