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PubMed2000

The HOPE Study (Heart Outcomes Prevention Evaluation).

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup. Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic). The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint. This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation. The HOPE study results show that it is both safe and beneficial to lower BP that is already within the 'normal' range, particularly in patients with known vascular risk factors. This should greatly extend the use of ACE-I to a wider group of patients - not only those with left ventricular dysfunction, hypertension or diabetic microalbuminuria, but to the sort of high-risk patients who are currently given prophylactic treatment with aspirin.

Aging↗

PubMed2004

Placebo-controlled trials in major depression are necessary and ethically justifiable: how to improve the communication between researchers and ethical committees.

Despite numerous placebo-controlled clinical trials with antidepressants were conducted in humans and a large amount of data was already published in the last two decades, the members of the 4th European Expert Forum on Ethical Evaluation of Placebo-Controlled Studies in Depression were agreed that placebo-controlled trials with antidepressants also in the future are essential. Placebo-controlled studies measure the effect size in a reliable way and establish sensitivity and internal validity. They are scientifically sound and interpretable in terms of efficacy and are, therefore, clinically more relevant than non-placebo-controlled clinical trials. The "Note of Clarification" of the Declaration of Helsinki opens up where such trials are acceptable. This statement of the members of the 4th European Expert Forum is directed to academia, members of Ethic Committees, regulators, and industry to facilitate their decisions towards clinical studies with antidepressants. "Checklists" for the contents of patients information are given as well as for the investigator.Placebo-controlled clinical trials are scientifically necessary, ethical and feasible. The administration of the placebo is in itself a non-specific treatment and experts agree that there appears to be no increased suicidal risk in the placebo-group of carefully selected and monitored study patients.

Antidepressive Agents↗

PubMed1999

Treatment of endotracheal or endobronchial obstruction by non-small cell lung cancer: lack of patients in an MRC randomized trial leaves key questions unanswered. Medical Research Council Lung Cancer Working Party.

Symptoms of endotracheal or endobronchial obstruction caused by non-small cell lung cancer (NSCLC) may be relieved with external beam radiotherapy (XRT) or endobronchial treatment. The comparative roles of these two methods need to be established. Patients with predominantly intraluminal obstruction of the trachea, a main bronchus or a lobar bronchus by unresectable NSCLC were randomized to XRT versus the clinician's choice of endobronchial treatment with brachytherapy, laser resection or cryotherapy, according to local availability and practice. Clinicians' assessments included symptoms of obstruction, WHO performance status, lung function tests and adverse effects of treatment. Patients completed a Rotterdam Symptom Checklist at all assessments and a daily diary card to record the severity of major symptoms during the first 4 weeks. To show a difference of 15% in the relief of breathlessness rates at 4 months (from 65% to 80%), 400 patients were required. In spite of our many previously successful lung cancer trials, and initial interest from clinicians in 24 UK centres, who estimated they could randomize 200 patients per year into the present trial, only 75 patients were randomized from seven centres over 3.5 years. Intake to the trial was therefore abandoned in November 1996 although an independent Data Monitoring and Ethics Committee had concluded in April 1996 that the scientific case for the trial was still strong; there were no competing trials; there were no design problems; and much had been done to promote the trial. The main reasons given by centres for the slow intake were: lack of referrals of untreated patients; patients being referred specifically for endobronchial treatment; patients having already received XRT; emergency endobronchial relief of obstruction being necessary; and XRT and endobronchial treatment being considered complementary and not as alternatives. The relative advantages and disadvantages of XRT versus endobronchial treatment remain to be determined. The lack of recruitment to this trial raises the issue of innovative techniques not being given the chance of proving their worth compared with traditional treatments.

Aged↗

PubMed1996

UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a complex and expensive technology that can be used to provide temporary support during respiratory failure. Its value for mature newborn infants is controversial because of varying interpretation of the available evidence. We undertook a collaborative trial throughout the UK to assess whether a policy of referral for ECMO has a beneficial effect on survival to 1 year without severe disability in comparison with conventional management. METHODS: Between 1993 and 1995, 185 mature (gestational age at birth > or = 35 weeks, birthweight > or = 2 kg) newborn infants with severe respiratory failure (oxygenation index > or = 40) were enrolled from 55 hospitals in a randomised comparison of either referral to one of five specialist centres for consideration of ECMO or continued intensive conventional management at the original hospital. The most common diagnoses were persistent pulmonary hypertension due to meconium aspiration, congenital diaphragmatic hernia, isolated persistent fetal circulation, sepsis, and idiopathic respiratory distress syndrome. Of the infants allocated ECMO, 84% received this support. Recruitment to the trial was stopped early (November, 1995) by the trial steering committee on the advice of the independent data-monitoring committee, because the data accumulated showed a clear advantage with ECMO. 124 children were enrolled before December, 1994; those who survived to 1 year of age have undergone neurological assessment at that age (by one of three developmental paediatricians unaware of treatment allocation). FINDINGS: Overall, 81 (44%) infants died before leaving hospital, and two are known to have died later. Death rates differed between the two trial groups; 30 of 93 infants allocated ECMO died compared with 54 of 92 allocated conventional care. The relative risk was 0.55 (95% Cl 0.39-0.77; p = 0.0005), which is equivalent to one extra survivor for every three to four infants allocated ECMO. The difference in survival applied irrespective of the primary diagnosis, disease severity, and type of referral centre. The benefit of ECMO was also found for the primary outcome measure of death or disability at 1 year (among 124 children enrolled before December, 1994). One child in each group has severe disability (overall Griffiths' developmental quotient < 50, or untestable), and 16 (ten ECMO, six conventional management) have impairments with a lesser degree of disability. INTERPRETATION: These preliminary results demonstrate the clinical effectiveness of a well-staffed and organised neonatal ECMO service. ECMO support should be actively considered for neonates with severe but potentially reversible respiratory failure.

Birth Weight↗

PubMed1996

Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party.

BACKGROUND: Single-drug oral etoposide daily for 5 days or more in 3-week cycles is commonly used as palliative chemotherapy for small-cell lung cancer (SCLC). However, there have been no randomised trials to compare this treatment with standard intravenous multidrug chemotherapy. Our objective was such a comparison in patients with poor performance status. However, before the planned intake of 450 patients had been completed the trial was stopped on the recommendation of an independent data monitoring committee, because of the inferiority of oral etoposide. We report the interim findings of the trial. METHODS: Patients of either sex and any age were entered into the trial if they had: previously untreated, microscopically confirmed SCLC; WHO grade performance status 2-4; no contraindications to either treatment regimen; normal renal function; and plasma bilirubin concentrations of less than 35 mumol/L. Patients with grade 4 performance status were likely to benefit from chemotherapy. Between September, 1992, and August, 1995, 339 patients were randomly allocated four cycles of 50 mg oral etoposide twice daily for 10 days (171 patients) or a standard intravenous regimen of etoposide and vincristine (EV), or cyclophosphamide, doxorubicin, and vincristine (CAV, 168 controls). The intake was stopped in September, 1995. Patients were assessed by clinicians before the start of treatment, at each attendance for treatment, at 3 months after randomisation, every month to 6 months, every 2 months to 1 year, then every 3 months thereafter. The primary endpoint was the palliation of major symptoms at 3 months after randomisation-ie, a reduction in cough, pain, anorexia, and shortness of breath scores. Secondary endpoints were quality of life, clinical and radiographic tumour response, and survival. FINDINGS: The palliative effects of treatment were similar in the etoposide group and control group (41% vs 46%). Grade 2 or worse haematological toxicity occurred in 35 (29%) etoposide-treated patients and 26 (21%) controls. Controls had a higher overall response rate than etoposide-treated patients (51% vs 45%). There was a small disadvantage in survival associated with oral etoposide (hazard ratio 1.35 [95% CI 1.03-1.79], p = 0.03). Median survival was 130 days in the etoposide group and 183 days in the controls; survival rates were 35% and 49% at 6 months and 11% and 13% at 12 months, respectively. INTERPRETATION: Oral etoposide 50 mg twice daily for 10 days every 3 weeks for four cycles is inferior to standard intravenous multidrug chemotherapy in the palliative treatment of patients with SCLC and poor performance status. Oral etoposide alone should no longer be used in the treatment of such patients.

Administration, Oral↗

PubMed1996

Approached to monitoring the results of long-term disease prevention trials: examples from the Women's Health Initiative.

We contrast monitoring therapeutic trials with monitoring prevention trails. We argue that in monitoring prevention trials one should place more emphasis on formally defined global measures of health, not simply on a single targeted disease, particularly when an intervention may reduce the incidence of some diseases but increase the incidence of others. We describe one approach, illustrated by the Women's Health Initiative. For each of several sets of hypothetical interim results ("scenarios"), members of the Data and Safety Monitoring Committee (DSMC) were asked whether they would continue or stop the trial. In parallel with this exercise, various statistical methods of monitoring that are based on (1) the primary targeted disease, (2) a combination of various disease outcomes, or (3) a mixture of both were applied to these scenarios. One objective was to find a statistical approach that mirrors the majority view of the DSMC. A second objective was to stimulate discussion among DSMC members in preparation for their task of monitoring the trial as the real data become available. We found that no single method fully matched the majority vote of the DSMC. However, a mixed approach requiring the primary outcome to be significant and the global index to be "supportive," with separate monitoring of adverse effects, corresponded with the majority vote quite well. This approach maintains the emphasis on the primary hypothesis while assuring that broader safety and ethical issues of multiple diseases are incorporated.

Bayes Theorem↗

PubMed2004

Endocrine aspects of female sexual dysfunction.

INTRODUCTION: Various endogenous hormones, including estrogen, testosterone, progesterone and prolactin, may influence female sexual function. AIM: To provide recommendations for the diagnosis and treatment of women with endocrinologic sexual difficulties. METHODS: The Endocrine Aspects of Female Sexual Dysfunction Committee was part of a multidisciplinary International Consultation. It included four experts from two countries and several peer reviewers. MAIN OUTCOME MEASURE: Expert opinion was based on committee discussion, a comprehensive literature review and evidence-based grading of available publications. RESULTS: The impact of hormones on female sexual function and their etiological roles in dysfunction is complex. Research data are limited as studies have been hampered by lack of precise hormonal assays and validated measures of sexual function in women. Sex steroid insufficiency is associated with urogenital atrophy and may also adversely affect central sexual thought processes. Systemic estrogen/estrogen progestin therapy alleviates climacteric symptoms but there is no evidence that this therapy specifically improves hypoactive sexual desire disorder (HSDD) in premenopausal or postmenopausal women. Exogenous testosterone has been shown in small randomized controlled trials (RCT) to improve sexual desire, arousal and sexual satisfaction in both premenopausal and postmenopausal women. However, as there is no biochemical measure that clearly identifies who to treat, use of exogenous testosterone should be considered only after other causes of HSDD have been excluded, such as depression, relationship problems and ill health. The clinical assessment of HSDD should include detailed medical, gynecologic, sexual and psychosocial history and physical examination including the external/internal genitalia. Hormonal therapy should be individualized and risks/benefits fully discussed, and all treated women should be carefully followed up and monitored for therapeutic side effects. CONCLUSIONS: There is a need for prospective, multi-institutional clinical trials to define safe and effective endocrine treatments for female sexual dysfunction.

Age Factors↗

PubMed2000

A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. MRC Testicular Tumour Working Party.

The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m(2)to be corrected for glomerular filtration rate outside the range 81-120 ml min(-1)and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60-82%) in patients allocated C and 81% (71-90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was - 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32-1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75-92%) in those allocated C, and 89% (81-96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35-2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies.

Antineoplastic Agents↗

PubMed2004

HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped.

In the 1990s, two randomised clinical trials started in Scandinavia addressing whether hormone replacement therapy (HRT) is safe for women with previous breast cancer. We report the findings of the safety analysis in HABITS (hormonal replacement therapy after breast cancer--is it safe?), an open randomised clinical trial with allocation to either HRT or best treatment without hormones. The main endpoint was any new breast cancer event. All analyses were done according to intention-to-treat. Until September, 2003, 434 women were randomised; 345 had at least one follow-up report. After a median follow-up of 2.1 years, 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event. All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003.

Breast Neoplasms↗

PubMed2006

Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases.

BACKGROUND AND PURPOSE: To investigate whether single-fraction radiotherapy is equal to multiple fractions in the treatment of painful metastases. PATIENTS AND METHODS: The study planned to recruit 1000 patients with painful bone metastases from four Norwegian and six Swedish hospitals. Patients were randomized to single-fraction (8 Gy x 1) or multiple-fraction (3 Gy x 10) radiotherapy. The primary endpoint of the study was pain relief, with fatigue and global quality of life as the secondary endpoints. RESULTS: The data monitoring committee recommended closure of the study after 376 patients had been recruited because interim analyses indicated that, as in two other recently published trials, the treatment groups had similar outcomes. Both groups experienced similar pain relief within the first 4 months, and this was maintained throughout the 28-week follow-up. No differences were found for fatigue and global quality of life. Survival was similar in both groups, with median survival of 8-9 months. CONCLUSIONS: Single-fraction 8 Gy and multiple-fraction radiotherapy provide similar pain benefit. These results, confirming those of other studies, indicate that single-fraction 8 Gy should be standard management policy for these patients.

Aged↗

PubMed1992

Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis.

BACKGROUND: In most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries. METHODS: In a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up. RESULTS: The study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P < 0.001). Major bleeding complications were infrequent and comparable in the two groups. CONCLUSIONS: Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy.

Acenocoumarol↗

PubMed1999

Mid-term results of a second generation bifurcated endovascular graft for abdominal aortic aneurysm repair: the French Vanguard trial.

PURPOSE: The purpose of this study was to evaluate prospectively the results of the bifurcated Vanguard endovascular graft for abdominal aortic aneurysm (AAA) repair. METHODS: Seventy-five patients, with a median age of 69.6 years (range, 48 to 88 years) and asymptomatic AAAs, were recruited in 14 French vascular institutions. An independent committee validated the indications for endovascular repair, and all the implantations were supervised by a well-trained medico-technical assistant. Further independent committees reviewed patient data, clinical data, and imaging follow-up examination. The main endpoints were implantation success, mortality, morbidity, reinterventions, and aneurysm evolution assessed with serial computed tomographic (CT) scanning. RESULTS: All the grafts were successfully implanted, resulting in a 100% success rate on an intent-to-treat basis. At discharge, there were no deaths, six significant local complications (8%) that necessitated surgery, no vascular complications, and six systemic complications (8%). The average durations of intensive care unit and hospital stays were 26 +/- 6 hours and 6 +/- 2.54 days, respectively. Predischarge CT scan results showed five type I and 18 type II endoleaks (total, 30%). At the end of the follow-up period (mean duration, 18.35 +/- 4.12 months; range, 17 days to 24 months), seven patients (9%) had died: one from sepsis, five from unrelated causes, and one from aneurysm rupture. The 2-year cumulative survival rate was 86% +/- 5.9%. Twenty-one subsequent endovascular or vascular procedures were necessitated (28%) in 17 patients (23%) to treat graft limb occlusion or stenosis (n = 9 patients) or to seal an endoleak (n = 8 patients). The 2-year cumulative survival rate free of reintervention was 67% +/- 7%. On CT scans, the mean AAA diameter decreased from 54 mm +/- 8.9 (range, 45 to 80 mm) before surgery to 51.6 mm +/- 9.1 at 6 months and to 43.4 mm +/- 4.4 at the end of the follow-up period (P =.001). Persistent endoleak was significantly associated with an increase in diameter (4 of 5 [80%] vs 1 of 47 [2%]; P =.001). CONCLUSION: In selected patients, the bifurcated Vanguard endovascular graft may be implanted with a low mortality and morbidity rate and a favorable mid-term survival rate. The decrease of the aneurysm size is a strong argument in favor of the efficiency of the device. However, lasting endoleaks with increased aneurysm diameter and occurrence of limb graft stenosis or occlusion raise concerns and justify a careful long-term follow-up monitoring of all patients who undergo treatment with endovascular technique.

Aged↗

PubMed1982

Pindolol: experience gained in 10 years of safety monitoring.

The benefit to be expected from any drug therapy should outweigh its inherent risk. All adverse events reported in connection with administration of pindolol have been carefully analyzed since this drug was marketed 10 years ago. The investigation included the data published in the literature, the information provided by spontaneous reporting or by bulletins issued by various national drug evaluation committees, and the results obtained by intensive hospital monitoring. This international surveillance reveals that pindolol elicits adverse reactions related to beta-adrenoceptor blockade; however, the incidence and especially the intensity of this type of side effect appear to be attenuated by the intrinsic sympathomimetic property exhibited by pindolol. Some other reported side effects, in general equally mild, cannot be explained by the known pharmacodynamic properties of pindolol. However, no specific toxicity has been observed even after long-term treatment. Taking into consideration that pindolol has been used for more than 3.7 million patient-years, it is certainly justified to assume that the full spectrum of adverse reactions that might be induced by this drug has been recognized and that in all probability no severe new untoward effects will be observed in the future.

Clinical Trials as Topic↗

PubMed2005

Ketamine for conscious sedation in pediatric emergency care.

The literature concerning the efficacy and safety of ketamine for conscious sedation during procedures in pediatric emergency departments was reviewed. Data were obtained from the Guidelines for Monitoring and Management of Pediatric Patients During and After Sedation for Diagnostic and Therapeutic Procedures developed by the American Academy of Pediatrics Committee on Drugs, and from a MEDLINE search (January 1966-July 2004). Search terms were conscious sedation, ketamine, and emergency department; articles relevant to pediatric age group were selected. Clinical end points were efficacy and adverse effects associated with ketamine. Ketamine was effective for conscious sedation in 89-100% of patients in various studies using intravenous, intramuscular, or oral routes of administration. The efficacy of ketamine was similar to or greater than that of other drugs, such as midazolam and the combination of meperidine, promethazine, and chlorpromazine. The main adverse effects of ketamine were emesis, recovery agitation, and emergence phenomena. Ketamine appears to be an effective and well-tolerated agent for conscious sedation in pediatric patients. Overall physician and parent satisfaction with the administration of this agent for conscious sedation was high.

Anesthetics, Dissociative↗

PubMed2006

ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Case for a European multicenter study.

PURPOSE: To present the development and design of the European Society of Cataract & Refractive Surgeons multicenter study of the prevention of postsurgical infective endophthalmitis after phacoemulsification and to describe the process for its successful implementation and conduct. SETTING: Twenty-four ophthalmology units and eye clinics in Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey, and the United Kingdom, with an administrative office in Ireland, coordinating center in England, and data management and statistical unit in Scotland. METHODS: This partially masked randomized placebo-controlled multinational clinical study was designed to evaluate prospectively the prophylactic effect of intracameral cefuroxime and/or perioperative topical levofloxacin on postoperative endophthalmitis after cataract surgery. Random allocation was based on a 2 x 2 factorial design that included participating centers as a class variable. Real-time electronic data collection monitored study progress and provided weekly outcome tables, monthly recruitment summaries, and quarterly analytical reports for the study's Data Monitoring Committee, which evaluated the safety and efficacy by Internet-based conferences. RESULTS: A 2-year lead time was required to meet harmonized standards of clinical research in the European Union, obtain ministerial authorization in 3 countries, gain institutional approvals at 24 hospitals, and procure indemnity insurance for surgical centers. Informed consent instruments, designed to comply with national health policies, were translated into 8 languages. The use of information technology to collect study data enabled the organizers to evaluate individual eligibility at enrollment, adherence with study medications during and after surgery, and postoperative status during follow-up. CONCLUSION: This international cooperative study provided the opportunity to estimate the current incidence of endophthalmitis after cataract surgery in Europe and determine whether 1 or both of 2 antimicrobial regimens reduces the risk for postsurgical intraocular infection.

Administration, Topical↗

PubMed1997

[Continuous measurements of cardiac output in the perioperative period].

Management of critically ill patients is based on knowledge of fundamental physiological variables. Automatized and continuous measurement of these variables is preferable. A new system based upon the thermodilution method has been developed to measure cardiac output automatically and continuously. We evaluated the system in the potentially unstable perioperative period with possible great and rapid changes in cardiac output. Twenty patients, scheduled for open heart or abdominal aortic aneurysm surgery, were included into the study, which was approved by the local ethical committee. The patients were monitored for up to 30 hours. At random intervals five iced bolus thermodilution cardiac output (BCO) determinations were made and compared to the continuous measurements (CCO). Two hundred and thirty-one pairs of data were obtained. The cardiac outputs ranged from 2.5-14.9 l/min. The absolute bias was 0.31 l/min (95% limits of agreement -1.4 l/min to 2.0 l/min). The mean relative error was 4.7% with a standard deviation of the relative error of 15.4%. The linear regression was represented by: CCO = 11.352 x BCO - 0.36. The correlation coefficient R was 0.90 (p < 0.001). In conclusion, the CCO measurement technique is a promising clinical method. The method is straightforward, requires no calibration, is independent of vascular geometry and measures with its limitations volumetric flow. Finally automatic and continuous patient monitoring provides more information and has potential to reveal previously undetected haemodynamic events.

Aged↗

PubMed2005

A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants.

BACKGROUND AND OBJECTIVE: Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved through the addition of peptides, such as sinapultide, that mimic the action of human surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non-protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived surfactant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syndrome (RDS) and RDS-related death. METHODS: We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of < or =32 weeks gestational age, to receive colfosceril palmitate (n = 509), lucinactant (n = 527), or beractant (n = 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dysplasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Primary outcomes, air leaks, and causes of death were assigned by an independent, masked, adjudication committee with prespecified definitions. The study was monitored by an independent data safety monitoring board. RESULTS: Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52-0.89). There was no significant difference in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25-0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18-0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less common with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56-0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45-1.00). CONCLUSIONS: Lucinactant is a more effective surfactant preparation than colfosceril palmitate for the prevention of RDS. In addition, lucinactant reduces the incidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: An intergroup study.

OBJECTIVE: Despite the improvement in progression-free and overall survival in patients with advanced ovarian cancer associated with platinum-taxane chemotherapy, strategies are needed to prevent the greater than 70% recurrence rate. METHOD: The Southwest Oncology Group (SWOG) initiated a phase III intergroup trial of alpha-interferon (IFNalpha-26, Schering-Plough, Kenilworth, NJ) in weekly doses of 50 x 10(6) IU (for 6 doses) versus observation only in patients with no pathological evidence of residual disease at second-look surgery in 1988. RESULTS: Patient accrual was extremely slow and the trial was permanently closed in 1999 by the SWOG Data and Safety Monitoring Committee with 74 registered patients. Of these patients, 70 were evaluable for progression-free and overall survival. There was no significant difference between the two study arms in relation to median progression-free survival (P = 0.56). The median survival duration associated with intraperitoneal alpha-interferon had not been reached versus 87 months on the observation arm. In general, intraperitoneal alpha-interferon was well tolerated. There were no treatment-related deaths or grade 4 adverse events. Although no efficacy conclusions can be drawn from this prematurely closed trial, it should be noted that 57% of the patients on the observation arm recurred and all died, whereas 63% recurred and only 43% died on the intraperitoneal alpha-interferon arm. CONCLUSION: Although this was a negative study, there should continue to be interest in the use of biological therapy to improve survival of patients in complete remission following primary chemotherapy.

Adult↗