Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial.

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. SUBJECTS/METHODS: 9804 males and females, aged ⩾55 years, with a body mass index of 27-45 kg m(-)(2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9±7.7 beats per minute (bpm) with weight increase; 1.4±7.3 bpm, 0-5 kg weight loss; 0.6±7.4 bpm, ⩾5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management.

Association between serum bilirubin and cardiovascular disease in an overweight high risk population from the SCOUT trial.

BACKGROUND AND AIMS: An inverse relationship between (serum) total bilirubin and risk of cardiovascular disease has been reported previously, but longitudinal data on overweight and obese patients are lacking. We have investigated the relationship between total bilirubin and cardiovascular adverse events in a large group of patients with risk factors for cardiovascular disease who were enrolled in a large weight loss trial. METHODS AND RESULTS: Data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial, including almost 10.000 overweight/obese high cardiovascular risk patients, were used. The relationship between total bilirubin level at screening and the primary outcome (i.e. non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death) for the entire study period was investigated using Cox proportional hazards models. The population was divided into four groups based on total bilirubin levels (normal range 5-25 µmol/L). Time-dependent Cox analyses were also performed to adjust for weight loss over time. Initial analyses adjusted for sex, age and treatment allocation showed significantly reduced hazard ratios of 0.80 (95% confidence interval 0.68-0.94), 0.73 (0.62-0.86) and 0.77 (0.65-0.91), for the three higher total bilirubin groups: >8 and ≤10 µmol/L, >10 and ≤13 µmol/L and >13 µmol/L (5-95 interpercentile range for total bilirubin at screening; 6-19 µmol/L), compared to the lowest total bilirubin group ≤8 µmol/L. When adjusting for classical cardiovascular risk factors, estimates increased towards unity. Additional adjustment for indicators of liver function did not alter the results. A time-dependent Cox model, adjusted for weight loss, demonstrated a similar trend. CONCLUSION: Bilirubin was not a risk-factor independent from other traditional cardiovascular risk-factors in our population.

Changes in body weight and blood pressure: paradoxical outcome events in overweight and obese subjects with cardiovascular disease.

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in body weight and blood pressure, and the impact of these changes on subsequent cardiovascular outcome events. SUBJECTS/METHODS: A total of 9804 male and female subjects, aged 55 years or older, with a body mass index of 27-45 kg m(-2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor (hypertension, dyslipidemia, current smoking or diabetic nephropathy) to assess cardiovascular outcomes. Post hoc subgroup analyses of weight change (categories) and blood pressure were performed overall and by treatment group (6-week sibutramine followed by randomized placebo or continued sibutramine). The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models with factors for treatment, subgroups and interactions. RESULTS: During the initial 6-week sibutramine treatment period, systolic blood pressure decreased progressively with increasing weight loss in hypertensive subjects (-8.1±10.5 mm Hg with <5 kg weight loss to -10.8±11.0 mm Hg with ⩾5 kg weight loss). The highest POE incidence occurred mainly in groups with increases in both weight and blood pressure. However, with long-term sibutramine treatment, a markedly lower blood pressure tended to increase POEs. CONCLUSION: Modest weight loss and modest lower blood pressure each reduced the incidence of cardiovascular events, as expected. However, the combination of early marked weight loss and rapid blood pressure reduction seems to be harmful in this obese elderly cardiovascular diseased population.

Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial.

AIM: The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored. METHODS: Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death). RESULTS: For the total population, mean weight change during Lead-in Period (sibutramine) was -2.54 kg. Post-randomization, mean total weight change to Month 12 was -4.18 kg (sibutramine) or -1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease. CONCLUSIONS: Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups.

The capsular bag after short- and long-term fixation of intraocular lenses.

PURPOSE: To investigate the effect of posterior chamber intraocular lens (PC IOL) size and construction on the capsular bag in human cadaver eyes. METHODS: Studies were done at two timeframes: (1) short term (prospective)--the effect of 12 different IOLs on the capsular bag configuration after experimental implantation; and (2) long term--(retrospective) analysis of eyes with PC IOLs obtained post-morterm. RESULTS: The short-term study showed the maximal diameter of the capsular bag to be 11.0 mm for IOLs with total diameter of 12.0 mm and 11.5 mm for 13.5- to 14.0-mm IOLs. Longer IOLs caused more ovaling of the bag with stress lines (striae) on the posterior capsule. Secondary processes such as proliferation of epithelial cells (Soemmering ring) and capsular fibrosis caused the capsular bag to resume a more circular shape with irregular contour. The area of contact between the IOL loops and the capsular equator was significantly lower in eyes with radial tears and IOLs with the J-loop design compared with the C-loop design. In both the short- and long-term groups, maximal capsular diameter did not exceed 12.0 mm. CONCLUSIONS: The results of this study suggest that using the capsulorrhexis technique, a 12.0-mm total diameter IOL is sufficient to provide stable capsular fixation.

Comparison of diode and argon laser trabeculoplasty in cadaver eyes.

PURPOSE: To evaluate differences in the effects of diode and argon trabeculoplasty on cadaver eye trabecular meshwork. METHODS: The argon laser was used at a 50 mu spot size, 500 to 100 mW of power, and a 0.1 second time interval, and the diode laser was used at a 0.1 to 0.2 second time interval, 100 mu spot size, and 400 to 1200 mW of power. Analysis was performed using videography, microscopy, and scanning electron microscopy. RESULTS: This study found grossly that burns with the argon laser caused tissue blanching and pigment dispersion, whereas no reaction was observed with the diode laser. The diode laser made no observable histologic alterations, but the argon caused fragmentation and coagulation of trabecular beams. Scanning electron microscopy showed that the diode laser caused an area of trabecular beam coalescence measuring 50 to 100 mu in diameter with energies > or = 0.12 J. A surrounding zone of more superficial trabecular beam fragmentation measuring 200 to 400 mu in diameter also was observed. Similar energy levels from the argon laser caused hole formation 200 to 400 mu in diameter. Lower argon energy levels (0.05 J) caused inconsistent coalescence 50 to 100 mu in diameter similar to the diode laser. CONCLUSIONS: This study suggests that in the trabecular meshwork the diode laser causes a reaction at, but not at less than, energy levels shown previously to produce a clinical ocular hypotensive effect. Also, at similar energy per area, the tissue effects of the diode and argon laser are comparable.

Clinicopathologic study of ocular trauma in eyes with intraocular lenses.

Data on 41 cases (37 intraocular lenses and four globes) of intraocular lenses explanted or expulsed after ocular trauma were retrieved from over 5,000 intraocular lenses and 1,200 globes. The age of the male and female donors varied significantly (male, 64.4 +/- 13.1 years; female, 75.5 +/- 12.6 years; P = .0334). Twenty-two were posterior chamber, 11 were anterior chamber, and eight were iris-fixated lenses. The mean implant durations were 0.66 +/- 0.9 years for posterior chamber intraocular lenses, 4.0 +/- 3.4 years for anterior chamber lenses, and 9.0 +/- 4.9 years for iris-fixated lenses. Accidental falling was the most common trauma in 14 of 21 cases (67%). In the posterior chamber intraocular lens group, trauma was more severe and resulted in rupture of the globe in 19 of 22 cases (86%) and expulsion of the intraocular lens in 15 of 22 cases (68%). Rupture usually occurred at the surgical wound, even when the trauma happened five years postoperatively. In contrast, most of the eyes with anterior chamber intraocular lenses and iris-fixated intraocular lenses did not rupture, but a minor trauma often resulted in intraocular lens dislocation and secondary complications that necessitated intraocular lens explantation. The pathologic findings were nonspecific (proteinaceous deposits, blood and pigment adherent to the intraocular lens). Severity of trauma and pathologic findings were not correlated. Posterior chamber intraocular lenses are more resistant to minor ocular trauma compared to anterior chamber and iris-fixated intraocular lenses.

[Configuration of the capsular sack after implantation of posterior chamber lenses]. / Konfiguration des Kapselsacks nach Implantation von Hinterkammerlinsen.

The effect of posterior chamber intraocular lenses (PC-IOLs) on the capsular bag was investigated in human cadaver eyes. Short-term changes were observed with different PC-IOLs directly after experimental implantation. Long-term results were obtained from postmortem eyes with PC-IOLs. Mean implant duration was 2.5 years. The average diameter of the capsular bag in the loop axis was 11.0 mm for 12.0 mm IOLs and 11.5 mm for 13.5-14.0 mm IOLs in the short-term study. Longer loops caused more ovaling of the bag with stress lines on the posterior capsule. The average diameter of the capsular bag in the long term study was 10.6 mm. Secondary processes such as capsular fibrosis and lens epithelial cell proliferation caused the capsular bag to shrink and thus to assume a more circular configuration. The area of contact between the IOL loops and the capsular equator was significantly lower in eyes with radial tears and IOLs with J-loop design when compared to C-loops. The maximal capsular diameter in both the long-term and short-term observations never exceeded 12.0 mm. The results of our study suggest that a 12.0 mm total diameter IOL is sufficient for stable fixation, provided that capsular bag implantation can be assured.

Inhibition of posterior capsule opacification: the effect of colchicine in a sustained drug delivery system.

We investigated the effect of colchicine in a sustained drug delivery system on posterior capsule opacification (PCO) in rabbit eyes. A polymer matrix wafer, which diffused colchicine at a steady rate, was implanted in the capsular bag of 34 eyes after the lens material was removed by endocapsular phacoemulsification. Three different drug concentrations were used in the rabbit eyes, which were compared with control eyes containing the polymer matrix wafer without colchicine. The mean PCO score was highest in the control group without colchicine and increased steadily over 12 weeks. The rate of PCO formation in all eyes treated with colchicine was significantly lower than in the control group. There was no statistically significant improvement in PCO inhibition with the higher colchicine dosages. Side effects included inflammatory anterior chamber reaction and corneal and retinal complications and were most notable with the highest drug concentration. Slow release of colchicine reduces PCO formation in the rabbit. The optimal biocompatible dosage must be carefully determined and warrants further investigation.

Experiences with GLP/GCP from the pharmaceutical industry's viewpoint.

The European Commission Directive 91/507/EEC has been enforced since January 1, 1992. It requires that all trials of a clinical development program be performed in compliance with Good Clinical Practice (GCP) guidelines which became effective on July 1, 1991 after approval by the CPMP in July 1990. Good Laboratory Practice (GLP) guidelines originated in the USA in 1978 and have been adopted in general in the OECD guidelines (OECD principles of Good Laboratory Practice, 1983) and in the appropriate national laws and guidelines, e.g., Chemikaliengesetz vom 14.3.1990, Germany. All GLP guidelines unambiguously address "non-clinical laboratory studies", for example, toxicological studies but not studies utilizing human subjects. The impact/non-impact of these guidelines is addressed by the day-to-day work in a clinical pharmacology unit within the pharmaceutical industry.

Clinicopathologic study of the effect of radial tears and loop fixation on intraocular lens decentration.

PURPOSE: The purpose of this study is to determine the effect of loop fixation and anterior capsular tears on intraocular lens (IOL) decentration. METHODS: A retrospective measurement of IOL decentration was performed on 144 human eyes with posterior chamber (PC) IOLs obtained after death. RESULTS: Decentration in eyes with asymmetrical bag-sulcus fixation (mean +/- standard deviation, 0.64 +/- 0.39 mm) was significantly higher than eyes with symmetrical fixation. In the presence of radial tears, symmetrically fixated IOLs in either the capsular bag or the ciliary sulcus decentered to a similar degree, 0.35 +/- 0.25 mm and 0.4 +/- 0.26 mm, respectively. The least decentration was observed with capsular fixation and no radial tears (0.18 +/- 0.09 mm). This was significantly less decentration than with any other form of fixation in the presence of radial tears. CONCLUSION: This study shows that capsular fixation with no radial tears, as can be achieved by using the continuous curvilinear capsulorhexis, is associated with the least decentration.

Loop memory of posterior chamber intraocular lenses of various sizes, designs, and loop materials.

Looped intraocular lenses (IOLs) fixate by exerting centripetal pressure on the ocular tissues. The ability of the flexible loops to maintain pressure depends on their rigidity (i.e., resistance to flexion) and their "memory" (i.e., ability to restore original configuration after a long period of compression). We studied the memory of 30 different posterior chamber IOLs, with loops made of polypropylene (PP) and poly(methyl methacrylate) (PMMA), of various diameters, styles, and designs. The lenses were inserted into plastic wells, 9.5 mm in diameter, and immersed in water (37 degrees C) for one month. They were then placed on an open plate and allowed to re-expand for one month. Loop memory was calculated as the difference in diameter between the initial (pretest) measurement and measurements taken during the compression and release periods. The results showed that short (12.0 to 12.5 mm) IOLs had relatively better memory than longer (13.5 to 14.0 mm) IOLs. Those with PP loops expanded more and for longer periods than those comparable size and design with PMMA loops. One-piece, all-PMMA lenses exhibited the best loop memory. These lenses have the high rigidity of the PMMA material and the good memory of the design. Thus, the total IOL diameter can be reduced to 12.0 mm while providing long-term constant pressure on the capsular bag to maintain stable fixation.

Prospective experimental study of factors related to posterior chamber intraocular lens decentration.

The effect of posterior chamber intraocular lens (IOL) dimensions, design, style, loop fixation, and anterior capsular tears on decentration were investigated in an experimental model. Nine posterior chamber IOLs of various designs and styles with loop diameters between 12.0 and 14.0 mm and optic diameters between 5.0 and 7.0 mm were implanted in human eyes obtained post mortem. Symmetrical and asymmetrical fixation were investigated in eyes with and without radial tears using the Miyake posterior view technique. Location of IOL loops proved to be the most significant factor in IOL decentration. Decentration was least with symmetrical bag/bag fixation and no radial tears (mean = 0.20 +/- 0.05 mm). Asymmetrical bag/sulcus fixation in the presence of anterior capsular tears was associated with the highest decentration rate (mean 0.68 +/- 0.28 mm). Optic size and total loop diameter had no apparent effect on IOL centration in the immediate postoperative period.

Posterior capsule opacification.

A complication of extracapsular cataract extraction with or without posterior chamber intraocular lens (PC-IOL) implantation is posterior capsule opacification. This condition is usually secondary to a proliferation and migration of residual lens epithelial cells. Opacification may be reduced by atraumatic surgery and thorough cortical clean-up. Clinical, pathological and experimental studies have shown that use of hydrodissection, the continuous curvilinear capsulorhexis and specific IOL designs may help reduce the incidence of this complication. Capsular-fixated, one-piece all-polymethylmethacrylate PC-IOLs with a C-shaped loop configuration and a posterior convexity of the optic are effective. Polymethylmethacrylate loops that retain "memory" create a symmetric, radial stretch on the posterior capsule after in-the-bag placement, leading to a more complete contact between the posterior surface of the IOL optic and the taut capsule. This may help form a barrier against central migration of epithelial cells into the visual axis. Various pharmacological and immunological methods are being investigated but conclusive data on these modalities are not yet available.

[Comparison of various capsulectomy techniques in cataract surgery. An experimental study]. / Vergleich verschiedener Kapsulektomietechniken in der Kataraktchirurgie. Eine experimentelle Studie.

Radial tears at the edge of an anterior capsulectomy are often associated with the occurrence of intraocular lens (IOL) loops coming out of the capsular bag with subsequent IOL decentration. We analyzed the incidence of radial tear formation in 40 human eyes obtained postmortem. These eyes were randomly assigned to four groups: "can opener," linear capsulotomy, capsulopuncture ("postage stamp"), and continuous curvilinear capsulorhexis (CCC). The CCC appeared to be much less likely to be associated with anterior capsular radial tears as opposed to the other three techniques. With the nucleus expression technique used in this study, radial tears occurred in all cases of "can opener," linear capsulotomy and capsulopuncture, whereas no tears occurred with the CCC technique. The results of this study show that CCC is currently the best available anterior capsulectomy procedure for minimizing the incidence of radial tears and sequelae such as decentration.

Scanning electron microscopic study of modern silicone intraocular lenses.

Silicone, as manufactured today, appears to be a biocompatible material. The safety and efficacy of silicone lenses are primarily related to the intraocular lens (IOL) design. We compared the edge finish of two three-piece polypropylene loop foldable silicone IOL designs (Allergan Medical Optics) and three one-piece designs (Staar Surgical Co., CooperVision-Cilco). Except for an early Staar one-piece design, all lenses including the more recent Staar lenses had acceptably smooth edges with minimal molding flash.

Posterior continuous curvilinear capsulorhexis. An experimental study with clinical applications.

The posterior continuous curvilinear capsulorhexis technique has been advocated in cases of posterior capsule rupture during extracapsular cataract extraction. The authors compared posterior continuous curvilinear capsulorhexis with posterior capsular sharp-edged tears. Two different types of forces were experimentally created on the posterior capsule of 30 human eyes obtained after death: (1) implantation and dialing of posterior chamber intraocular lenses (PC IOLs) and (2) increased intravitreal pressure by injection of balanced salt solution. All posterior capsular tears extended toward the equator, causing major capsular defects. In contrast, the posterior continuous curvilinear capsulorhexis remained intact in all cases. This experimental study proves that in cases where an inadvertent posterior capsular tear occurs, a posterior continuous curvilinear capsulorhexis is useful in preventing further capsular damage. Also, in cases where a posterior capsulotomy is indicated, a smooth edge created by a posterior continuous curvilinear capsulorhexis may be useful to maintain the integrity of the capsular bag for PC IOL capsular implantation.

A comparison of neodymium: yttrium aluminum garnet and diode laser transscleral cyclophotocoagulation and cyclocryotherapy.

The cyclodestructive effects of cyclocryotherapy and of the neodymium:yttrium aluminum garnet (Nd:YAG) and diode laser transscleral cyclophotocoagulation were investigated in phakic and pseudophakic cadaver eyes using a modified Miyake posterior-view technique and light microscopy. Cyclocryotherapy to -80 degrees C was applied with a 2.5-mm diameter tip, 1 and 2 mm from the limbus. Freezing at the ciliary processes was evident after 10-15 sec and reached a diameter of 3-4 mm by 30 sec. No visible changes were evident grossly in the ciliary processes, crystalline lens, or intraocular lens. Histologically increased separation of cells was observed. Effective noncontact Nd:YAG and diode laser applications to the ciliary processes were observed grossly as tissue blanching and shrinking and pigment dispersion. This effect was obtained by aiming 0.5-1.0 mm behind the limbus at a 1-mm defocus using 4 J of energy for the Nd:YAG and 1.2 J for the diode laser. The diode laser spot size did not affect the tissue response. No damage was observed in the crystalline or intraocular lens with either type of laser. Histologic changes using both lasers were coagulation necrosis with fragmentation and detachment of the ciliary body epithelium. This study suggested that the gross and histologic thermal effects produced by the diode and Nd:YAG laser were similar in the ciliary body. Also, at the time of surgery, these cyclodestructive procedures potentially cause little alteration of the crystalline or intraocular lens.

The relationship between the stretching capability of the anterior capsule and zonules.

The stretching capability of the zonules was studied in 40 human eyes obtained postmortem from 27 patients. A continuous circular capsulorhexis (CCC) (2.2-6.8 mm) was performed, and the lenses were removed by either phacoemulsification (26 eyes) or planned extracapsular cataract extraction (ECCE) (14 eyes). Maximal zonular stretch was calculated as the difference in distance between the ciliary processes and the zonular insertion at rest and after maximal stretch. This zonular stretch test showed that zonules can stretch to a mean distance of 3.82 mm before rupturing. Capsular elasticity was measured in 35 of the eyes by gradually opening a modified caliper until the capsular opening was torn. The ratio between the circumference at rupture and the circumference at rest was used as an index of capsular elasticity. Circumference of the intact capsulorhexis could be enlarged an additional 62% before a radial tear occurred. In most cases, no significant correlation was seen between the capsular and zonular capability to stretch. Maximal zonular stretch decreased significantly with age by approximately 0.5 mm for every 5 yr, whereas capsular elasticity did not show a significant correlation with age. Two eyes with pseudoexfoliation had relatively friable zonules but the capsular elasticity was within normal limits. Patient age is probably the best indicator of the stretching capability of the zonules.