Amy Chen Rundle

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion: Six-Month Primary End Point Results of a Phase III Study

PURPOSE To assess the efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after central retinal vein occlusion (CRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 392 patients with macular edema after CRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 12.7 (9.9-15.4) and 14.9 (12.6-17.2) in the 0.3 mg and 0.5 mg ranibizumab groups, respectively, and 0.8 (-2.0 to 3.6) in the sham group (P<0.0001 for each ranibizumab group vs. sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 46.2% (0.3 mg) and 47.7% (0.5 mg) in the ranibizumab groups and 16.9% in the sham group (P<0.0001 for each ranibizumab group vs. sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg = 43.9%; 0.5 mg = 46.9%) had BCVA of > or = 20/40 compared with sham patients (20.8%; P<0.0001 for each ranibizumab group vs. sham), and CFT had decreased by a mean of 434 microm (0.3 mg) and 452 microm (0.5 mg) in the ranibizumab groups and 168 microm in the sham group (P<0.0001 for each ranibizumab group vs. sham). The median percent reduction in excess foveal thickness at month 6 was 94.0% and 97.3% in the 0.3 mg and 0.5 mg groups, respectively, and 23.9% in the sham group. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with CRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid improvement in 6-month visual acuity and macular edema following CRVO, with low rates of ocular and nonocular safety events.

Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE

PURPOSE To evaluate the efficacy and safety of intravitreal ranibizumab in diabetic macular edema (DME) patients. DESIGN Two parallel, methodologically identical, phase III, multicenter, double-masked, sham injection-controlled, randomized studies. PARTICIPANTS Adults with vision loss from DME (best-corrected visual acuity [BCVA], 20/40-20/320 Snellen equivalent) and central subfield thickness ≥275 μm on time-domain optical coherence tomography (OCT). INTERVENTION Monthly intravitreal ranibizumab (0.5 or 0.3 mg) or sham injections. Macular laser was available per-protocol-specified criteria. MAIN OUTCOME MEASURES Proportion of patients gaining ≥15 letters in BCVA from baseline at 24 months. RESULTS In RISE (NCT00473330), 377 patients were randomized (127 to sham, 125 to 0.3 mg, 125 to 0.5 mg). At 24 months, 18.1% of sham patients gained ≥15 letters versus 44.8% of 0.3-mg (P<0.0001; difference vs sham adjusted for randomization stratification factors, 24.3%; 95% confidence interval [CI], 13.8-34.8) and 39.2% of 0.5-mg ranibizumab patients (P<0.001; adjusted difference, 20.9%; 95% CI, 10.7-31.1). In RIDE (NCT00473382), 382 patients were randomized (130 to sham, 125 to 0.3 mg, 127 to 0.5 mg). Significantly more ranibizumab-treated patients gained ≥15 letters: 12.3% of sham patients versus 33.6% of 0.3-mg patients (P<0.0001; adjusted difference, 20.8%; 95% CI, 11.4-30.2) and 45.7% of 0.5-mg ranibizumab patients (P<0.0001; adjusted difference, 33.3%; 95% CI, 23.8-42.8). Significant improvements in macular edema were noted on OCT, and retinopathy was less likely to worsen and more likely to improve in ranibizumab-treated patients. Ranibizumab-treated patients underwent significantly fewer macular laser procedures (mean of 1.8 and 1.6 laser procedures over 24 months in the sham groups vs 0.3-0.8 in ranibizumab groups). Ocular safety was consistent with prior ranibizumab studies; endophthalmitis occurred in 4 ranibizumab patients. The total incidence of deaths from vascular or unknown causes, nonfatal myocardial infarctions, and nonfatal cerebrovascular accidents, which are possible effects from systemic vascular endothelial growth factor inhibition, was 4.9% to 5.5% of sham patients and 2.4% to 8.8% of ranibizumab patients. CONCLUSIONS Ranibizumab rapidly and sustainably improved vision, reduced the risk of further vision loss, and improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

The VIVA Trial

Background—Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF. Methods and Results—A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng · kg−1 · min−1), or high-dose rhVEGF (50 ng · kg−1 · min−1) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups (placebo, +48 seconds; low dose, +30 seconds; high dose, +30 seconds). Angina class and quality of life were significantly improved within each group, with no difference between groups. By day 120, placebo-treated patients demonstrated reduced benefit in all three measures, with no significant difference compared with low-dose rhVEGF. In contrast, high-dose rhVEGF resulted in significant improvement in angina class (P =0.05) and nonsignificant trends in ETT time (P =0.15) and angina frequency (P =0.09) as compared with placebo. Conclusions—rhVEGF seems to be safe and well tolerated. rhVEGF offered no improvement beyond placebo in all measurements by day 60. By day 120, high-dose rhVEGF resulted in significant improvement in angina and favorable trends in ETT time and angina frequency.

Ranibizumab for Macular Edema following Central Retinal Vein Occlusion

PURPOSE To assess efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema following branch retinal vein occlusion (BRVO). DESIGN Prospective, randomized, sham injection-controlled, double-masked, multicenter clinical trial. PARTICIPANTS A total of 397 patients with macular edema following BRVO. METHODS Eligible patients were randomized 1:1:1 to receive monthly intraocular injections of 0.3 mg or 0.5 mg of ranibizumab or sham injections. MAIN OUTCOME MEASURES The primary efficacy outcome measure was mean change from baseline best-corrected visual acuity (BCVA) letter score at month 6. Secondary outcomes included other parameters of visual function and central foveal thickness (CFT). RESULTS Mean (95% confidence interval [CI]) change from baseline BCVA letter score at month 6 was 16.6 (14.7-18.5) and 18.3 (16.0-20.6) in the 0.3 mg and 0.5 mg ranibizumab groups and 7.3 (5.1-9.5) in the sham group (P<0.0001 for each ranibizumab group vs sham). The percentage of patients who gained > or =15 letters in BCVA at month 6 was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the sham group (P<0.0001 for each ranibizumab group vs sham). At month 6, significantly more ranibizumab-treated patients (0.3 mg, 67.9%; 0.5 mg, 64.9%) had BCVA of > or =20/40 compared with sham patients (41.7%; P<0.0001 for each ranibizumab group vs sham); and CFT had decreased by a mean of 337 microm (0.3 mg) and 345 microm (0.5 mg) in the ranibizumab groups and 158 microm in the sham group (P<0.0001 for each ranibizumab group vs sham). The median percent reduction in excess foveal thickness at month 6 was 97.0% and 97.6% in 0.3 mg and 0.5 mg groups and 27.9% in the sham group. More patients in the sham group (54.5%) received rescue grid laser compared with the 0.3 mg (18.7%) and 0.5 mg (19.8%) ranibizumab groups. The safety profile was consistent with previous phase III ranibizumab trials, and no new safety events were identified in patients with BRVO. CONCLUSIONS Intraocular injections of 0.3 mg or 0.5 mg ranibizumab provided rapid, effective treatment for macular edema following BRVO with low rates of ocular and nonocular safety events.

Long-term Outcomes of Ranibizumab Therapy for Diabetic Macular Edema: The 36-Month Results from Two Phase III Trials: RISE and RIDE

PURPOSE To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME). DESIGN Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years. PARTICIPANTS Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography. METHODS Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary. MAIN OUTCOME MEASURES The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24. RESULTS Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group. CONCLUSIONS The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Participants in the National Registry of Myocardial Infarction 2

Numerous large clinical trials of thrombolytic therapy have shown impressive reductions in mortality associated with the use of thrombolytic agents in the setting of acute myocardial infarction. They have also consistently shown that thrombolysis imposes an excess risk for intracranial hemorrhage [1]. Although the incidence of intracranial hemorrhage associated with thrombolytic therapy is low, this complication is characterized by high fatality rates and substantial disability among survivors. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator (tPA) for Occluded Coronary Arteries (GUSTO-I) trial, intracranial hemorrhage rates were 0.46%, 0.57%, 0.70%, and 0.88% among patients treated with streptokinase plus subcutaneous heparin, streptokinase plus intravenous heparin, accelerated tPA, and combination therapy, respectively. Sixty percent of patients who had intracranial hemorrhage died, and another 25% were disabled [2]. The underuse of thrombolysis in special patient populations, such as elderly persons, is usually attributed to concerns about the risk for bleeding, particularly intracranial hemorrhage [3, 4]. These concerns often dominate decisions about the use of thrombolytic agents in eligible elderly patients with acute myocardial infarction despite the potential for substantial survival benefits from treatment [1]. In the GUSTO-I trial [5], 0.42% of patients younger than 75 years of age treated with streptokinase and 0.52% of those treated with accelerated tPA experienced a hemorrhagic stroke by 30 days of follow-up. Among patients older than 75 years of age, these values were 1.23% and 2.08%, respectively. Simoons and colleagues [6] combined information from a national registry of thrombolytic therapy with data from multiple thrombolytic trials to identify 150 patients who had had intracranial hemorrhage and compared them with 294 patients with acute myocardial infarction who received thrombolytic therapy but did not experience this outcome. After adjustment for other factors, including type of thrombolytic agent, body weight, and presence of hypertension on admission, patients older than 65 years of age were significantly more likely to experience intracranial hemorrhage (odds ratio, 2.2 [95% CI, 1.4 to 3.5]). Most information on the risk for intracranial hemorrhage associated with thrombolytic therapy in acute myocardial infarction derives from the experience of patients participating in clinical trials, in which stringent enrollment criteria are applied before thrombolytic therapy is administered [2, 7, 8]. The experience in the community setting has not been well described. The extent to which the clinician can extrapolate clinical trial data on the benefits and the risks of therapeutic interventions to the general practice setting is often unclear [9]. We used data from an ongoing national registry of patients who were hospitalized for acute myocardial infarction to determine the frequency of and risk factors for intracranial hemorrhage in patients treated with tPA, with particular focus on the relation between advancing age and this complication. Methods Data Sources The National Registry of Myocardial Infarction 2 (NRMI 2) was initiated in June 1994 as an ongoing registry of patients who received therapy for acute myocardial infarction at selected U.S. hospitals. The registry is supported by Genentech, Inc. (South San Francisco, California). From 1 June 1994 to 30 September 1996, 1484 U.S. hospitals contributed patients to NRMI 2. Participation in the registry is voluntary. Registry hospitals are substantially larger than nonparticipating U.S. hospitals: Twenty-seven percent of registry hospitals have more than 350 beds compared with 8% of nonregistry hospitals. In addition, registry hospitals are more likely than nonregistry hospitals to be certified by the Joint Commission on Accreditation of Health Care Organizations (99% compared with 77%); be affiliated with a medical school (36% compared with 17%); and have a coronary care unit (73% compared with 31%), a cardiac catheterization laboratory (72% compared with 23%), and a cardiac surgery program (39% compared with 11%). Registry hospitals are encouraged to enter consecutive patients who have had acute myocardial infarction, regardless of treatment or outcome. Approval for hospital participation in the registry may include review by the local institutional review board or human research subjects committee as dictated by local policy. A study coordinator at each participating hospital completes individual data collection forms for each study patient; these forms are forwarded to an independent central data collection center (ClinTrials Research, Inc., Lexington, Kentucky) for processing. Data on individual hospitals are confidential and are available only to the contributing hospital. Patients Patients in our study had had acute myocardial infarction documented according to local hospital criteria (usually cardiac enzyme levels or results of electrocardiography or coronary angiography). For the purpose of our study, patients were those enrolled in NRMI 2 who received tPA as the initial reperfusion strategy from 1 June 1994 to 30 September 1996. To be eligible for study inclusion, patients could not have been transferred to a participating registry hospital from any other hospital (registry or otherwise) in the context of management of the acute myocardial infarction event. In addition, study patients could not have received a second dose of any thrombolytic agent. As of 30 September 1996, NRMI 2 included 389 130 patients. Of these, 99 694 had received tPA as the initial reperfusion strategy; 26 370 of these patients had been transferred from another hospital for treatment of acute myocardial infarction. Of the remaining 73 324 patients, 2115 had received a second dose of a thrombolytic agent and 136 patients had missing information on age or sex. This left 71 073 patients in the study sample. The number of study patients contributed per registry hospital ranged from 1 to 311. Definitions The occurrence of primary intracranial hemorrhage was indicated on the registry data collection form, along with the date and time of onset of neurologic symptoms and whether computed tomography or magnetic resonance imaging (MRI) was performed to confirm the event. Events reported to have been confirmed by computed tomography or MRI were of principal interest in our study. The time between administration of tPA and intracranial hemorrhage was calculated. Sequelae of intracranial hemorrhage were characterized as death during hospitalization, residual deficit at discharge, or no residual deficit at discharge. The magnitude of the residual deficit was not classified. The reported intracranial hemorrhages and the circumstances surrounding them were not independently verified; information on these events was limited to that available on the data collection form provided by the participating hospitals. We characterized patients according to age (<65 years, 65 to 74 years, or 75 years), sex, and ethnicity (white, black, or other). Clinical characteristics included history of myocardial infarction, angina, congestive heart failure, coronary artery bypass graft or percutaneous transluminal coronary angioplasty, stroke, diabetes mellitus, hypertension, hypercholesterolemia, and smoking. Systolic and diastolic blood pressure were characterized according to the first measurement recorded at hospital presentation. Likewise, Killip class was measured at presentation (no evidence of congestive heart failure, presence of rales or jugular venous distention, pulmonary edema, or cardiogenic shock) [10]. The study sample was stratified into quartiles according to body weight (measured in kg). The dose of tPA administered was categorized as less than 1.5 mg/kg or 1.5 mg/kg or more. These categories were based on manufacturer recommendations for tPA dosing [11]. (For patients weighing >67 kg, the maximum recommended total tPA dose is 100 mg [ 1.49 mg/kg]. Dosage adjustments based on weight are advised for patients weighing 67 kg or less.) Duration of tPA infusion was categorized as 90 minutes or less (accelerated tPA) or more than 90 minutes. We also characterized patients according to use of aspirin or intravenous heparin, which may be relevant to risk for bleeding. Statistical Analysis To assess comparability with a large clinical trial population, selected characteristics of our study sample were compared with those of patients who received accelerated tPA plus intravenous heparin in the GUSTO-I trial [5]. For our study sample, we evaluated the bivariate association between intracranial hemorrhage and selected demographic and clinical patient characteristics. These variables were used to develop stepwise multivariable logistic regression models with the occurrence of intracranial hemorrhage (confirmed by computed tomography or MRI) as the dependent variable. Patients with unknown values for any variable were excluded from multivariable analyses. The models were constructed with an entry significance level of P = 0.01 and an exit significance level of P = 0.05. Estimated odds ratios for the risk for intracranial hemorrhage, adjusted for all remaining variables, were obtained by using this model. Interactions between patient age and all other variables remaining in the final regression model were assessed. The goodness-of-fit criteria of Hosmer and Lemeshow were assessed for all models [12]. In addition, we calculated an area under the receiver-operating characteristic curve for each model [13]. All tests of statistical significance were two-tailed; a P value less than 0.05 was considered statistically significant. Multiple logistic regression analyses were performed by using the SAS PROC LOGISTIC procedure in SAS, version 6 (SAS Institute, Inc., Cary, North Carolina). The main-effects models were refit by using SAS PROC PHREG to control for potential int

Bundle-Branch Block and In-Hospital Mortality in Acute Myocardial Infarction

Complete left or right bundle-branch block (BBB) on electrocardiography at presentation has been reported to occur in 1% to 15% of patients with acute myocardial infarction, and it has been associated with increased risk for short- and long-term death [1-19]. Left BBB is considered an important predictor of poor outcome in patients with myocardial infarction [20, 21], but the effect of right BBB is less well-understood and has received relatively little attention [22-24]. Previous studies have reported a wide range of mortality rates in patients with acute myocardial infarction and left BBB (19% to 65%) [4, 6, 8-1012-15, 19] or right BBB (11% to 77%) [3-58, 9, 11-1315-17, 19]. However, although some studies suggest that left or right BBB is an independent predictor of in-hospital death in patients with acute myocardial infarction [11, 12, 19], others have found either no effect [9] or an effect dependent on age [25] or location of infarction [16, 17]. Previous studies had small numbers of patients with BBB [1, 2, 4, 5, 9-19, 25]; were done in the prethrombolytic era [1, 2, 4-68, 10, 13-18, 25]; did not compare both left and right BBB in the same population [11, 16, 17]; or did not assess the association of BBB with adverse outcomes after adjustment for potential confounding by differences in clinical characteristics, location of infarction, and treatment [1-19, 25]. To address these problems, we studied 297 832 patients with acute myocardial infarction to estimate the prevalence of left and right BBB, compare the clinical characteristics of and treatments received by patients, and assess the association of left and right BBB with in-hospital death. Methods Data Source and Study Sample The National Registry of Myocardial Infarction (NRMI) 2 is a voluntary, prospective, observational registry that includes patients with acute myocardial infarction from all 50 states who were admitted to participating U.S. hospitals. The data set for our analysis included 510 044 patients from 1571 hospitals enrolled between 1 June 1994 and 30 April 1997. A trained registry coordinator at each participating hospital retrospectively reviewed charts and recorded information on individual patients onto standardized case report forms. Completed forms were processed by an independent central data collection center. Extensive electronic data checks were done; errors in the forms were resolved before patient data were included in the database [26]. We analyzed 297 832 patients who were at least 18 years of age and were admitted to participating hospitals with confirmed acute myocardial infarction, which was defined on the basis of typical symptoms and signs accompanied by 1) a total creatine kinase level or creatine kinase-MB fraction at least twice the upper limit of normal; 2) electrocardiographic evidence of acute myocardial infarction; 3) other enzymatic, scintigraphic, echocardiographic, or autopsy evidence indicating myocardial infarction; or, if the preceding three variables were unavailable, 4) a principal discharge diagnosis of acute myocardial infarction (code 410, International Classification of Diseases, 9th Revision, Clinical Modification). The diagnosis of myocardial infarction was not independently validated. Patients who were transferred to or out of a participating hospital (n = 212 212) were excluded from the cohort to ensure that data on demographic characteristics, clinical presentation, myocardial infarction care, and in-hospital death were more complete. Measurements The main predictor variable was the presence of left or right BBB on the first 12-lead electrocardiogram, which was ascertained from responses on case report forms describing initial electrocardiography results. Diagnosis of left or right BBB was not independently validated. Information on the timing of onset (new or old) or persistence of BBB was not collected. Data on the presence of left anterior or posterior fascicular block were unavailable. The small proportion of patients identified with both left and right BBB (0.1%; n = 410) was categorized as having left BBB for the purpose of our analysis. Our results were not significantly affected by the inclusion or exclusion of these patients, and we therefore included them in all analyses. Other predictor variables included age, sex, ethnicity (white, black, or other/unknown), cardiovascular history (previous myocardial infarction, angina, congestive heart failure, stroke, percutaneous transluminal coronary angioplasty [PTCA], or coronary artery bypass graft surgery [CABG]), known cardiac risk factors (diabetes mellitus, hypertension, current cigarette smoking, family history of coronary heart disease, or hypercholesterolemia), chest pain at admission, interval between symptom onset and arrival at the hospital, body weight, systolic and diastolic blood pressure at admission, heart rate at admission, Killip class, and location of infarction. If more than one infarction location was noted, patients were hierarchically assigned to the category with the worst prognosis: anterior, which could include any other specified category; right ventricular involvement, which could include any other specified category except anterior; inferior, which could include any other specified category except anterior and right ventricular involvement; and other/unknown, which included all remaining categories other than anterior, right ventricular involvement, and inferior and also included patients with unspecified location of infarction and patients with nondiagnostic electrocardiograms. The main outcome variable was in-hospital death. Secondary clinical outcome variables were in-hospital cardiovascular events other than death: development of congestive heart failure, hypotension requiring treatment, cardiogenic shock, recurrent ischemia or angina, second- or third-degree heart block, and cardiac arrest. Process-measure outcome variables included use of intravenous thrombolytic therapy, location at which thrombolytic therapy was initiated (emergency department, intensive care or cardiac care unit, or catheterization laboratory/other), time from symptom onset to initiation of thrombolytic therapy, time from arrival at the hospital to initiation of thrombolytic therapy, reason for not using thrombolytic therapy (advanced age, nondiagnostic electrocardiogram, duration of symptoms, other contraindications, or other/reason not specified), use of primary PTCA, use of initial reperfusion strategies other than PTCA (immediate CABG or intracoronary thrombolytic therapy), medical therapies given within the first 24 hours (aspirin, -blockers, heparin, nitroglycerin, angiotensin-converting enzyme [ACE] inhibitors, or calcium-channel blockers), elective PTCA, elective CABG, and pacemaker insertion. Statistical Analysis Demographic and clinical characteristics of, treatments received by, and outcomes for patients with left, right, or no BBB were compared by using the Student t-test or the Wilcoxon rank-sum test for continuous variables and the chi-square test for proportions. All pairwise comparisons were made. All analyses were planned a priori and were treated with equal importance. Only P values of 0.001 or less were considered statistically significant, and any significant differences were assessed for clinical importance. No additional adjustments were made for multiple comparisons [27]. We used logistic regression models to evaluate the independent association of left BBB and right BBB with in-hospital death; patients with no BBB and no ST-segment elevation served as the reference group. In model 1, we adjusted for 1) differences in baseline demographic and clinical variables previously shown to affect risk for in-hospital death in patients with acute myocardial infarction and 2) any other variables associated with in-hospital death on bivariate analyses with a P value less than 0.01. In model 2, we included all of the variables from model 1 and added treatment variables previously shown to be related to in-hospital death, including time-dependent use of intravenous thrombolytic therapy or primary PTCA (<6 hours, 6 to 12 hours, or >12 hours from symptom onset); use of aspirin, -blockers, or ACE inhibitors within the first 24 hours; and in-hospital CABG. On the basis of an a priori hypothesis, we also tested for an interaction between left or right BBB and the presence of chest pain at presentation. Only a minimal interaction was found between left BBB and chest pain on stratified analyses; therefore, results of models without interaction terms are presented. All analyses were done by using SAS statistical software, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source Two of the authors are employees of Genentech, Inc. (South San Francisco, California). One of the authors is a consultant for Genentech, Inc., and is on the NRMI Advisory Board. The funding source sponsored the development of NRMI 2 and provided funding for data analysis. The funding source works in conjunction with an independent NRMI Advisory Board made up of nationally recognized experts in cardiology and emergency medicine. The final version of the manuscript was reviewed by a member of the NRMI Advisory Board. Results Prevalence of Bundle-Branch Block and Patient Characteristics The prevalence of right BBB on the first 12-lead electrocardiogram was 6.2% (95% CI, 6.1% to 6.3%); the prevalence of left BBB was 6.7% (CI, 6.6% to 6.8%) (Table 1). Table 1. Characteristics of 297 832 Patients with Acute Myocardial Infarction with and without Bundle-Branch Block at Presentation in the National Registry of Myocardial Infarction 2 (1 June 1994-30 April 1997)* Compared with patients with no BBB, patients with right or left BBB were more likely to be older; to be white; and to have a history of infarction, angina, congestive heart failure, CABG, stroke, diabetes mellitus, and hypertension. The proportion of female patients was greater among pat

Slipped Capital Femoral Epiphysis in Children Treated with Growth Hormone

We examined the association between slipped capital femoral epiphysis (SCFE) and growth hormone (GH) treatment in 16,514 children who had not been treated with GH prior to their enrollment in the Nati

Intraocular Pressure in Eyes Receiving Monthly Ranibizumab in 2 Pivotal Age-Related Macular Degeneration Clinical Trials

PURPOSE To characterize preinjection intraocular pressure (IOP) in eyes receiving monthly ranibizumab versus sham or verteporfin photodynamic therapy (PDT) for age-related macular degeneration (AMD). DESIGN Post hoc analysis of IOP data from 2 phase 3 clinical trials, the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) trial. PARTICIPANTS All safety-evaluable patients who received 1 or more injections of sham or PDT or of ranibizumab and had 1 or more postbaseline IOP measurements recorded for the study eye. METHODS Preinjection IOP measurements for study eyes (n = 1125) and fellow eyes in MARINA and ANCHOR at baseline and at each monthly visit through month 24 were analyzed. MAIN OUTCOME MEASURES End points evaluated were maximum preinjection IOP during the 24-month treatment period; any occurrence of absolute preinjection IOP of 21 mmHg or more, 25 mmHg or more, or 30 mmHg or more; any occurrence of IOP increase of 6 mmHg or more, 8 mmHg or more, or 10 mmHg or more from baseline; any combination of IOP increase of 6 mmHg or more or 8 mmHg or more from baseline with concurrent absolute preinjection IOP of 21 mmHg or more or 25 mmHg or more; glaucoma-related adverse events; new glaucoma medications used for 45 days or more; and glaucoma filtration or laser surgeries. RESULTS Across treatment groups, 60.1% to 70.9% of study eyes had a maximum preinjection IOP of less than 21 mmHg. Comparing ranibizumab 0.5 mg versus sham or PTD treatment, respectively: 39.9% versus 29.1% and 10.9% versus 5.1% had maximum preinjection IOPs of 21 mmHg or more or 25 mmHg or more, respectively; 44.1% versus 29.9% and 24.2% versus 13.6% had IOP increases from baseline of 6 mmHg or more or 8 mmHg or more, respectively; 26.1% versus 13.6% and 16.8% versus 9.0% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 21 mmHg or more; 9.6% versus 3.7% and 7.5% versus 2.4% had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, respectively, with a concurrent IOP of 25 mmHg or more. No differences were observed in fellow eyes. CONCLUSIONS Most ranibizumab-treated eyes did not experience sustained preinjection IOP of 21 mmHg or more (>2 consecutive visits) over 24 months. When evaluating the combined IOP end point, more ranibizumab-treated eyes had 1 or more IOP increase from baseline of 6 mmHg or more or 8 mmHg or more, with concurrent highest IOPs of 21 mmHg or more and 25 mmHg or more versus sham or PDT. Intraocular pressure should be monitored in eyes receiving ranibizumab.

Reperfusion therapy for acute myocardial infarction: observations from the National Registry of Myocardial Infarction 2

The National Registry of Myocardial Infarction 2 (NRMI-2) provides a unique opportunity to evaluate the practice patterns among participating cardiology and emergency medicine departments involved in the care of patients with acute myocardial infarction. The data from NRMI-2 suggest that almost 1/3 of all non-transfer-in and non-transfer-out patients are eligible for reperfusion therapy. Furthermore, of those patients who are clearly eligible for reperfusion therapy, 24% are not given this proven therapy. Specifically, women, the elderly, patients without chest pain on presentation, and those patients at highest risk for in-hospital mortality were least likely to be treated with reperfusion therapy. The reason for underuse of reperfusion therapy may in part reflect a concern for adverse bleeding events associated with the use of thrombolytic therapy. The data from NRMI-2 also suggest that patients with contraindications to thrombolysis may be very appropriate for primary angioplasty. Realizing the full potential benefits of reperfusion therapy in terms of reduced cardiovascular morbidity and mortality will require that clinical practice patterns be aligned more closely with the recommended national guidelines, which are based on extensive clinical trial data that show the benefit of reperfusion therapy in a wide range of patients with acute myocardial infarction. By using observational databases, such as the NRMI-2, which describe how clinical care is administered in nonclinical trial settings, we can continually monitor our progress and initiate changes to ensure that patients are given access to the many therapies that have been shown to improve their quality of life and survival.