Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis.

BACKGROUND: A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's more favorable adverse-event profile compared with tricyclic antidepressants (TCAs). OBJECTIVES: The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted. METHODS: Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups. RESULTS: The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients. CONCLUSIONS: Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.

Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose.

BACKGROUND: The efficacy and safety of fluoxetine in adults with moderate-to-severe major depression are well established. However, most analyses combined dosages (20-80 mg/day) of the compound. We hypothesized that in patients taking 20 mg/day, efficacy would be maintained but the incidence of adverse events would be lower. We present a meta-analysis of efficacy and safety data for fluoxetine, 20 mg/day. METHOD: Data were from 3 double-blind studies (N = 417) that included patients with moderate-to-severe major depression (DSM-III or DSM-III-R criteria) who received placebo or fixed-dose 20-mg/day treatment with fluoxetine. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D; HAM-D-17 total score and anxiety/somatization, retardation, sleep disturbance, and cognitive disturbance factors) and response and remission rates. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, and adverse events leading to discontinuation. Adverse events were evaluated to determine the emergence of activation and/or sedation. RESULTS: At 20 mg/day, fluoxetine-treated patients demonstrated significantly greater remission and response rates and mean changes on HAM-D-17 total score and anxiety/somatization, retardation, and cognitive disturbance factor scores than placebo-treated patients (p < .001). The incidence of specific adverse events leading to discontinuation and the frequency of study discontinuations due to adverse events were similar among fluoxetine-treated and placebo-treated patients (6.1% vs. 5.8%, p = .879). Several adverse events (insomnia, asthenia, somnolence, gastroenteritis, decreased libido, chills, and confusion) occurred significantly more frequently among fluoxetine-treated patients. A significant change in sedation, but not activation, occurred in patients in the fluoxetine 20-mg/day group compared with the placebo group. CONCLUSION: These data affirm that fluoxetine at 20 mg/day is efficacious, safe, and of similar activation potential when compared with placebo in patients with major depression.

Risk factors for corneal graft failure.

BACKGROUND: Penetrating keratoplasty is one of the most common and successful ophthalmic procedures. However, controversy and uncertainty still call to question the significance of certain risk factors for graft failure. METHODS: A consecutive series of 1819 penetrating keratoplasties at a single center was studied to determine donor and recipient risk factors for graft failure. Mean follow up was 2.3 years (range, 1 to 96 months) with 139 (7.7%) eyes lost to follow up. RESULTS: Previous graft failure was the most significant risk factor for secondary failure (P = .0013). The risk of failure significantly decreased with increased postoperative time. Significant patient risk factors for secondary failures in initial grafts included race (P = .01), age (P = .004), iris color (P = .02), use of preoperative glaucoma medications (P = .0008), deep stromal vascularization (P = .002), and host horizontal diameter (P = 0.007). Significant risk factors for failures associated with immunologic allograft reactions in initial grafts included horizontal corneal diameter (P = .002), donor size (P = .05), differences between horizontal corneal diameter, and both donor size (P = .02) and recipient trephination size (P = .01). However, deep stromal vascularization was only marginally significant (P = .09). A history of preoperative glaucoma medication usage was not a significant risk factor. CONCLUSIONS: The relationship of the recipient's horizontal corneal diameter to immunologic graft rejection is a new risk factor that surgeons can directly control and thereby help avoid graft failure.

Automated lamellar keratomileusis in situ for myopia.

BACKGROUND: Keratomileusis in situ, particularly automated lamellar keratoplasty, is a commonly performed technique of keratomileusis in the United States. METHODS: A single center consecutive series of 152 eyes undergoing keratomileusis in situ for myopia was analyzed. Spherical equivalent refractions were compared before and after surgery. The standard nomogram supplied with the automatic corneal shaper (Chiron Vision Corp, Irvine, Calif) was used. The mean of preoperative myopia treated was -9.30 +/- 3.10 diopters (D) (range, -5.12 to -22.75 D). RESULTS: Of the 144 eyes with 1 month follow up, 30 (21%) were within 0.50 D of the planned correction at 1 month, 54 (38%) were within 1.00 D, and 97 (67%) were within 2.00 D. At 6 or more months follow up, 51 of 68 eyes (75%) achieved uncorrected visual acuity of 20/40 or better and 13 of 68 (19%) 20/20 or better when eyes with macular degeneration and amblyopia were removed. Forty-six of 78 eyes (59%) with 6 months or greater follow up required retreatment procedures to correct residual myopia or astigmatism. Multiple regression analysis explained 40% of the variation between attempted correction and postoperative results. An overall 5% shift of refraction in the myopic direction occurred between 1 and 6 months. Of the 110 eyes with both 1- and 3-month examinations, the spherical equivalent refraction changed between these time intervals by 1.00 D or more in 54 (49%) eyes; and 11 (31%) eyes changed by 1.00 D or more between the 3- and 6-month examinations. Although 6% of eyes lost 2 or more lines of spectacle-corrected visual acuity, 11% gained 2 or more lines. CONCLUSION: Myopic keratomileusis in situ using the automated lamellar keratoplasty technique appears to be a safe and most effective procedure to reduce moderate to high myopia. However, the predictability of the procedure needs improvement.

Arcuate transverse keratotomy for astigmatism followed by subsequent radial or transverse keratotomy. ARC-T Study Group. Astigmatism Reduction Clinical Trial.

BACKGROUND: We studied the safety and efficacy of arcuate transverse keratotomy performed for the primary correction of naturally occurring corneal astigmatism. METHODS: A multicenter, prospective evaluation of one-stage arcuate transverse keratotomy was conducted in 160 eyes with 1.00 to 6.00 diopters (D) of naturally occurring astigmatism. Vector analysis was used. After 1 month, those eyes that needed further refractive surgery received radial keratotomy for myopia and second-stage arcuate transverse keratotomy for residual astigmatism. RESULTS: Mean preoperative refractive cylinder was 2.80 D. At 1 month, the vector-corrected change was 2.30 D. Eighty-eight (61%) eyes had at least 1.00 D of residual refractive cylinder and 24 (17%) had at least 2.00 D. Eyes undergoing a second surgery averaged 1.60 D of vector-corrected effect, for a total effect of 2.90 D from both surgeries, indicating the astigmatic refractive effects were not additive. Eyes that had radial keratotomy alone as the second surgery demonstrated a similar change in refractive cylinder as eyes that had both radial and transverse keratotomies. Two eyes lost two lines of spectacle-corrected visual acuity, 29 eyes lost one line, 84 showed no change, and 26 eyes improved one line. CONCLUSION: Arcuate transverse keratotomy reduced refractive astigmatism. Both overcorrection and undercorrection were common. Complications were infrequent but occasionally caused significant irregular astigmatism. Arcuate transverse keratotomy appears to be a safe procedure with few complications.

Astigmatism reduction clinical trial: a multicenter prospective evaluation of the predictability of arcuate keratotomy. Evaluation of surgical nomogram predictability. ARC-T Study Group.

OBJECTIVE: To determine the accuracy of the Lindstrom surgical nomogram for astigmatism. DESIGN: A prospective multicenter study. PATIENTS: One hundred sixty eyes of 95 patients underwent astigmatic keratotomy in eight centers by nine surgeons. Inclusion criteria for the study included age of at least 18 years with 1 to 6 diopters (D) of naturally occurring corneal astigmatism and less than 1 D of lenticular astigmatism. INTERVENTIONS: A standardized astigmatic keratotomy surgical technique was performed on each eye. Surgical measurements were determined using the Lindstrom surgical nomogram for astigmatism. MAIN OUTCOME MEASURE: The Holladay, Cravy, Koch vector analysis method was used to determine the change in refractive cylinder results. Refractive changes also are presented without vector analysis merely using the absolute change in refractive cylinder and axis. RESULTS: Multiple regression analysis was used to develop a mathematical model determining the factors predictive of the change in refractive cylinder. The significant predictors for the amount of astigmatic correction achieved were, in order of decreasing importance, the following: number of incisions (R2 = 30%), incision length (R2 = 16%), age (R2 = 8%), and gender (R2 = 2%). CONCLUSIONS: Astigmatism is a two-dimensional measurement of both quantity and direction that is most appropriately analyzed with vector analysis. The original Lindstrom surgical nomogram for arcuate keratotomy used in this study is still quite useful although it tended to underpredict results for many patients, especially those having two incisional surgeries. Some older subjects having minimal surgery achieved greater correction than predicted by the original nomogram. The most important factors predictive of greater astigmatic keratotomy surgical effect are incision number, incision length, older age, and male gender.

Corneal tissue levels of topically applied ciprofloxacin.

The effectiveness of the fluoroquinolone ciprofloxacin is dependent on stromal drug concentrations which exceed the minimum inhibitory concentration90 (MIC90). The purpose of this study is to compare corneal tissue ciprofloxacin levels in patients exposed to three ciprofloxacin dosing regimens before undergoing penetrating keratoplasty. Thirty-one patients were assigned to one of three treatment groups. Group 1 followed a ciprofloxacin dosing regimen compatible with home use [two drops of 0.3% ciprofloxacin (Ciloxan; Alcon Laboratories, Fort Worth, TX, U.S.A.) every 4 h over a 24-h period]. Groups 2 and 3 followed a more tightly controlled dosing regimen designed for a health-care setting (two drops of Ciloxan applied by a trained professional every 15 min over a 4-h period). In groups 1 and 2, corneal epithelium was left intact, whereas in group 3 corneas were abraded. Corneal tissue samples were surgically obtained. Excised buttons were frozen and Ciloxan concentration determined by high-pressure liquid chromatography. Ciloxan corneal tissue concentrations (mean +/- SD) were 8.82 +/- 8.24 micrograms/g tissue in group 1, 166.20 +/- 336.94 micrograms/g tissue in group 2, and 938.30 +/- 1,081.51 micrograms/g tissue in group 3. Ciloxan penetration can be improved by administering the drug in a controlled setting at 15-min intervals over a 4-h period. Individual Ciloxan concentrations exceeded the MIC90 for most key ocular pathogens despite wide variability in all experimental groups.