Composite Outcome Measure Research Articles

An analysis of relationship between quality of life indices and clinical improvement following intervention in patients with intermittent claudication due to femoropopliteal disease

To establish the relationship between quality of life (QOL) index scores and clinical indicators of lower limb ischemia. One hundred seventy-eight patients (108 men, median age 70 years) with femoropopliteal lesions suitable for angioplasty were recruited. Assessments were performed prior to and at 1, 3, 6, and 12 months following intervention (angioplasty and/or supervised exercise program). Clinical indicators of lower limb ischemia (treadmill walking distances, ankle pressures), generic (SF36, EuroQol), and disease-specific (Kings College VascuQol) quality of life questionnaires were analyzed. Correlation analysis was performed for index scores (SF-6D, EQ-5D, VascuQol) and individual domain scores using nonparametric tests. All clinical indicators of lower limb ischemia and quality of life index scores showed a statistically significant improvement as result of intervention (Friedman test, P < .001). Both generic QOL index scores (SF-6D, EQ-5D) showed moderate but statistically significant correlation (Spearman's rank correlation, P < .001) with treadmill walking distances (SF-6D r = 0.533, EQ-5D r = 0.500) and weak but significant correlation to resting and postexercise ankle-brachial pressure index (SF-6D r = 0.253, EuroQol r = 0.214). Disease-specific index scores (VascuQol) showed similar moderate correlation to treadmill walking distances (r = 0.584, P < .001) and weak but statistically significant correlation with resting and postexercise ABPI (r = 0.377, P < .001). All index scores showed strong and statistically significant (P< .001) correlation with patient-reported walking distance (SF-6D r = 0.604, EQ-5D r = 0.511, VascuQol r = 0.769). All domains of SF36 showed similar correlation with clinical indicators except general health. The strongest correlation was seen with treadmill walking distances in the domains of physical function (r = 0.538) and bodily pain (r = 0.524). All generic and disease-specific QOL scores show statistically significant improvement with angioplasty and/or supervised exercise in patients with claudication due to femoropopliteal atherosclerosis. However, the degree of improvement seen in clinical indicators of lower limb ischemia is not reflected in these scores. These findings support the use of composite outcome measures with mandatory, independent assessment of QOL as an independent outcome measure in intervention studies in these patients.

Correlation of 2-Methoxyestradiol Levels in Cord Blood and Complications of Prematurity

2-methoxyestradiol (2ME2) is a potent antiangiogenic molecule that inhibits the expression of hypoxia-inducible factor (HIF)-1alpha and, consequently, of VEGF and other HIF-1alpha target genes. Although 2ME2 is elevated during pregnancy in maternal serum, its presence in fetal fluids and its impact in neonatal health are unknown. In this study, we 1) described normal levels of 2ME2 in maternal blood, cord blood, breast milk, and amniotic fluid, and 2) compared a composite measure of perinatal outcome between infants born with high and low levels of 2ME2. We found that 2ME2 was significantly decreased in all fluids compared with prepartum maternal serum. After stratifying babies by 2ME2 exposure levels, we observed no differences in the vulnerability to impaired lung development or to complications involving aberrant angiogenesis or vascular leak, such as necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), posthemorrhagic hydrocephalus (PHH), and retinopathy of prematurity (ROP). In summary, fetal 2ME2 concentrations do not appear to affect neonatal outcome.

Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT)

Objective To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term.Design Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention...

Trial sequential analyses of meta-analyses of complications in laparoscopic vs. small-incision cholecystectomy: more randomized patients are needed

Objective Conclusions based on meta-analyses of randomized trials carry a status of “truth.” Methodological components may identify trials with systematic errors (“bias”). Trial sequential analysis (TSA) evaluates random errors in meta-analysis. We analyzed meta-analyses on laparoscopic vs. small-incision cholecystectomy regarding different outcome measures for the occurrence of type I errors. Study Design and Setting Using TSA, we calculated the required information size (IS) and the trial sequential monitoring boundaries regarding complications in our Cochrane review with meta-analyses of cholecystectomy. For each outcome, we calculated a low risk of bias heterogeneity-adjusted IS. As a sensitivity analysis, we calculated an a priori heterogeneity-adjusted IS. Results According to the trial sequential analyses based on a low risk of bias heterogeneity-adjusted IS definitive evidence may be reached by conducting one more randomized trial. Information may be required on 582 and 119 additional randomized patients to evaluate the effect on severe complications and serious adverse events (SAEs), respectively. Conclusion Our results provide incentives to conduct a new trial with a low risk of bias focusing on a new composite outcome measure of SAEs to obtain conclusive evidence on which operative method to recommend.

Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial

Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. ZonMw.

Paclitaxel-Eluting Stents versus Bare-Metal Stents in Acute Myocardial Infarction

There is no consensus regarding the safety and efficacy of drug-eluting stents, as compared with bare-metal stents, in patients with ST-segment elevation myocardial infarction who are undergoing primary percutaneous coronary intervention (PCI). We randomly assigned, in a 3:1 ratio, 3006 patients presenting with ST-segment elevation myocardial infarction to receive paclitaxel-eluting stents (2257 patients) or otherwise identical bare-metal stents (749 patients). The two primary end points of the study were the 12-month rates of target-lesion revascularization for ischemia (analysis powered for superiority) and a composite safety outcome measure of death, reinfarction, stroke, or stent thrombosis (powered for noninferiority with a 3.0% margin). The major secondary end point was angiographic evidence of restenosis at 13 months. Patients who received paclitaxel-eluting stents, as compared with those who received bare-metal stents, had significantly lower 12-month rates of ischemia-driven target-lesion revascularization (4.5% vs. 7.5%; hazard ratio, 0.59; 95% confidence interval [CI], 0.43 to 0.83; P=0.002) and target-vessel revascularization (5.8% vs. 8.7%; hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P=0.006), with noninferior rates of the composite safety end point (8.1% vs. 8.0%; hazard ratio, 1.02; 95% CI, 0.76 to 1.36; absolute difference, 0.1 percentage point; 95% CI, -2.1 to 2.4; P=0.01 for noninferiority; P=0.92 for superiority). Patients treated with paclitaxel-eluting stents and those treated with bare-metal stents had similar 12-month rates of death (3.5% and 3.5%, respectively; P=0.98) and stent thrombosis (3.2% and 3.4%, respectively; P=0.77). The 13-month rate of binary restenosis was significantly lower with paclitaxel-eluting stents than with bare-metal stents (10.0% vs. 22.9%; hazard ratio, 0.44; 95% CI, 0.33 to 0.57; P<0.001). In patients with ST-segment elevation myocardial infarction who were undergoing primary PCI, implantation of paclitaxel-eluting stents, as compared with bare-metal stents, significantly reduced angiographic evidence of restenosis and recurrent ischemia necessitating repeat revascularization procedures. No safety concerns were apparent at 1 year. (ClinicalTrials.gov number, NCT00433966.)

Risk Factors for Severe Disease in Adults with Falciparum Malaria

Over a 16-year period, we conducted a clinical study of malaria acquired worldwide in adults from malaria-nonendemic countries, to determine risk factors for severe Plasmodium falciparum malaria. All patients with confirmed malaria who were managed by our unit from 1991 to 2006 were prospectively evaluated. Factors predicting disease severity according to (1) strict World Health Organization (WHO) criteria, (2) a composite measure of unfavorable outcome, and (3) length of hospital stay were identified by logistic and linear regression analyses. We evaluated 676 episodes of malaria, 482 (71%) due to P. falciparum and 194 (29%) due to nonfalciparum parasites. Black patients had a significantly reduced risk of developing WHO-defined severe falciparum malaria, with Asian patients having odds of severe falciparum malaria that were 8.05-fold (95% confidence interval [CI], 2.93-22.1-fold) higher and white patients having odds that were 8.20-fold (95% CI, 2.94-22.9-fold) higher. Black patients also had a reduced risk of an unfavorable outcome and of a prolonged stay in the hospital, compared with the risks for white or Asian patients. Of 6 patients with falciparum malaria who died, none were black. In univariate analysis, patients with parasitemias of >or= 2% had odds of severe falciparum malaria 12-fold higher than those of patients with parasitemias of <2% (73% vs. 19%). Patients with a history of previous clinical malaria, regardless of ethnicity, had a significantly reduced risk of WHO-defined severe falciparum malaria (odds ratio, 0.35 [95% CI, 0.15-0.80]). The findings of this study demonstrate that ethnicity and parasitemia are important independent risk factors for severe falciparum malaria in adults from malaria-nonendemic countries and that a history of previous clinical malaria significantly reduces the risk of WHO-defined severe falciparum malaria.

Raised C-reactive protein on ICU discharge is not associated with subsequent poor outcome

It has been suggested that plasma C-reactive protein (CRP) levels measured on discharge from the ICU may be a useful predictor of either unplanned readmission or unexpected death on the ward. Previous work has found that raised plasma CRP independently predicted, in separate studies, each of these two poor outcomes [1,2]. We investigated whether these results could be repeated in our mixed medical/surgical ICU for a composite poor outcome measure combining death and readmission.

Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?

To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART. Observational cohort study of patients initiating ART between January 2000 and December 2005. The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. A total of 13 546 antiretroviral-naïve HIV-positive patients initiating ART with efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). Compared with efavirenz as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; nevirapine (adjusted odds ratio = 1.87, 95% confidence interval (CI) = 1.58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1.04-1.56) and abacavir (1.22, 95% CI = 1.00-1.48). Among antiretroviral-naïve patients initiating therapy, between-ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

Donepezil Treatment of Severe Alzheimer’s Disease in Nursing Home Settings. A Responder Analysis

Background/Aims: Our objective was to define clinically meaningful outcomes in donepezil versus placebo treatment in severe Alzheimer’s disease (AD) and to describe characteristics of responders. Methods: Analyses were performed on data from a 6-month, double-blind, parallel-group, placebo-controlled study on the efficacy of donepezil in 248 nursing home residents. Various individual responses were defined as stabilisation or improvement on the Severe Impairment Battery (SIB), Alzheimer’s Disease Cooperative Study-activities of daily living scale (ADCS-ADL), Mini-Mental State Examination, Neuropsychiatric Inventory (NPI) or Clinical Global Impression of Improvement. Three composite measures were defined by combining the individual response criteria on these outcomes. The impact of baseline disease severity and of concomitant use of psychotropic drugs was also analysed. Results: At 6 months, greater proportions of patients defined as responders to donepezil on individual efficacy measures showed significant stabilisation or improvement compared with placebo on the SIB (≧0, ≧4 or ≧7 points) and Mini-Mental State Examination (≧0 or ≧3 points), and positive trends on the ADCS-ADL-severe (≧3 points) and the NPI cluster based on mood items. All 3 composite measures of efficacy showed a significantly higher proportion of responders in the donepezil group. The responders had a similar distribution between the 2 subgroups of cognitive and functional disease severity at baseline. The donepezil-treated patients taking psychotropic drugs showed significantly greater improvement on the SIB, less deterioration on the ADCS-ADL, and had higher Clinical Global Impression of Improvement scores and a trend towards lower NPI scores. The baseline demographic and clinical profile did not differ between the non-responders and responders on the composite outcome measures. Conclusion: The results demonstrate that donepezil treatment of patients with severe AD consistently shows stabilisation or improvement across multiple outcome measures in individual patients, including cognitive, functional and behavioural symptoms.

Low-Molecular-Weight Heparin versus Compression Stockings for Thromboprophylaxis after Knee Arthroscopy

Knee arthroscopy, the most common orthopedic operation worldwide, carries a definite risk for deep venous thrombosis; however, postsurgical thromboprophylaxis is not routinely recommended. To evaluate whether low-molecular-weight heparin (LMWH) better prevents deep venous thrombosis and does not cause more complications than graduated compression stockings in adults having knee arthroscopy. Assessor-blind, randomized, controlled trial. The Department of Knee Surgery, Abano Terme Clinic, Abano Terme (knee surgery, random assignment, and bleeding event survey), and the Unit of Angiology, University Hospital of Padua, Padua (efficacy outcomes evaluation, follow-up, data management, and analysis), Italy. 1761 consecutive patients undergoing knee arthroscopy between March 2002 and January 2006. Patients were randomly assigned to wear full-length graduated compression stocking for 7 days (660 patients) or to receive a once-daily subcutaneous injection of LMWH (nadroparin, 3800 anti-Xa IU) for 7 days (657 patients) or 14 days (444 patients). The data and safety monitoring board prematurely stopped the 14-day heparin group after the second interim analysis. Combined incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality (primary efficacy end point) and combined incidence of major and clinically relevant bleeding events (primary safety end point). All patients had bilateral whole-leg ultrasonography at the end of the allocated prophylactic regimen or earlier if indicated. All patients with normal findings were followed for 3 months, and none was lost to follow-up. The 3-month cumulative incidence of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality was 3.2% (21 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, 2.3 percentage points [95% CI, 0.7 to 4.0 percentage points]; P = 0.005), and 0.9% (4 of 444 patients) in the prematurely stopped 14-day LMWH group. The cumulative incidence of major or clinically relevant bleeding events was 0.3% (2 of 660 patients) in the stockings group, 0.9% (6 of 657 patients) in the 7-day LMWH group (absolute difference, -0.6 percentage point [CI, -1.5 to 0.2 percentage points]), and 0.5% (2 of 444 patients) in the 14-day LMWH group. The study was not double-blind or double-dummy. Almost half of the events making up the composite outcome measure were distal deep venous thromboses. Stockings were used instead of placebo because of local prophylaxis policies. In patients undergoing knee arthroscopy, prophylactic LMWH for 1 week reduced a composite end point of asymptomatic proximal deep venous thrombosis, symptomatic venous thromboembolism, and all-cause mortality more than did graduated compression stockings.

The valuation of prenatal life in economic evaluations of perinatal interventions

Perinatal interventions delivered during the prenatal period have the potential to directly impact prenatal life. The decision on when to begin 'counting' the life of an infant in the calculus has received little attention in previous economic evaluations of perinatal interventions. We illustrate, using data from a recent trial-based economic evaluation of magnesium sulphate given to women with pre-eclampsia to prevent eclampsia, how different definitions of when human life commences can have a significant impact upon cost-effectiveness estimates based on composite outcome measures such as life years or quality-adjusted life years gained or disability-adjusted life years averted. Further, we suggest ways in which methods in this area can be improved.

Rockall Risk Stratification of Non-Variceal Upper GI Bleed in a Community Teaching Hospital and Its Accuracy in the Setting of Pro-Hemorrhagic Medications

• Outcome measures included level of care, repeat endoscopy, repeat bleed, re-admission within 30 days since day of discharge, death or surgery during hospital stay and within 30 days of discharge, any blood transfusion and blood transfusion greater than 4 units of packed red blood cells. A composite outcome measure was also formulated which included repeat endoscopy, greater than two units of PRBC transfused, re-admission within 30 days, re-bleed, surgery and/or death.

Cohort profile: the Centers for AIDS Research Network of Integrated Clinical Systems

Highly active antiretroviral therapy (HAART) delays disease progression and death. However, the treatments incompletely control HIV replication, only partially restore immune function, have significant shortand long-term toxicities, and eventually fail in many patients with consequent development of HIV drug resistance. Thus, there is increasing need for information to guide HIV-infected patients and their providers in making decisions regarding optimal use of antiretroviral therapies. Although clinical trials provide valuable information about efficacy and side effects of antiretroviral treatment, they have limited size, duration and power to detect effects on clinical outcomes, focusing instead on surrogate endpoints such as virologic failure, treatment discontinuation or composite outcome measures. Outside the clinical trial setting, there is tremendous heterogeneity among HIV-infected patients. The prevalence and impact of important health conditions such as hepatitis C virus (HCV) co-infection, mental illness and substance abuse likely contribute to increased toxicity and decreased clinical effectiveness of HAART regimens among the broader spectrum of patients treated in routine care. Cohorts with significant diversity in HIV disease severity, comorbidities and demographic distributions are required to provide information regarding long-term outcomes and complications of HIV infection in the modern HAART era. The Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) was created to better define the relationship between patient and treatment factors and long-term clinical outcomes among HIV-infected patients in the HAART era. The CFARs are a national network of centres of excellence for HIV care and research established by the National Institutes of Health (NIH) whose mission is to support a multi-disciplinary environment for basic, clinical, epidemiologic, behavioural and translational research in the prevention, detection and treatment of HIV infection and AIDS. There are 19 CFARs located at academic and research institutions throughout the United States. The objective of the CNICS project is to integrate clinical data from the large and diverse population of HIV-infected persons receiving care at CFAR sites to investigate questions related to HIV disease management that cannot be readily addressed through traditional randomized controlled clinical trials and other cohort studies. Investigators with expertise in basic, clinical, translational and epidemiologic research, in addition to medical informatics, are collaborating on the CNICS project. The potential to build a comprehensive clinical data repository for HIV disease was greatly advanced by the work of CFAR investigators at the participating CNICS sites who had instituted point-of-care electronic medical record systems (EMRs) with the dual purpose of providing real-time clinical information to facilitate the delivery of HIV care and capturing standardized clinical data to support populationbased HIV research. The initial four CNICS sites were Case Western Reserve University, University of * Corresponding author. Center for AIDS Research, University of Washington, 325 9th Ave, MS 359931, Seattle, WA 98104, USA. E-mail: kitahata@u.washington.edu 1 Department of Medicine, University of Washington, Seattle, 98195, USA. 2 Department of Medicine, Case Western Reserve University, Cleveland, 44106, USA. 3 Department of Medicine, University of California, San Diego, 92110, USA. 4 Department of Medicine, Harvard University, Boston, 02115, USA. 5 Department of Medicine, Johns Hopkins University, Baltimore, 21218, USA. 6 Department of Medicine, University of Alabama, Birmingham, 35209, USA. 7 Department of Medicine, University of California, San Francisco, 94143, USA. Published by Oxford University Press on behalf of the International Epidemiological Association

Population Management, Systems-Based Practice, and Planned Chronic Illness Care: Integrating Disease Management Competencies into Primary Care to Improve Composite Diabetes Quality Measures

The increasing prevalence of chronic illnesses in the United States requires a fundamental redesign of the primary care delivery system's structure and processes in order to meet the changing needs and expectations of patients. Population management, systems-based practice, and planned chronic illness care are 3 potential processes that can be integrated into primary care and are compatible with the Chronic Care Model. In 2003, Harvard Vanguard Medical Associates, a multispecialty ambulatory physician group practice based in Boston, Massachusetts, began implementing all 3 processes across its primary care practices. From 2004 to 2006, the overall diabetes composite quality measures improved from 51% to 58% for screening (HgA1c x 2, low-density lipoprotein, blood pressure in 12 months) and from 13% to 17% for intermediate outcomes (HgA1c <or=7, low-density lipoprotein <or=100, systolic blood pressure <or=130). Over the same period, a secondary retrospective cohort analysis noted greater gains in composite screening and intermediate outcome measures for patients with planned visits compared to those who had no planned visits. This study illustrates how 1 delivery system integrated these disease management functions into the front lines of primary care and the positive impact of those changes on overall diabetes quality of care.

Almotriptan: meeting today’s needs in acute migraine treatment

Migraine is a common disorder associated with considerable individual and economic burden. Triptans are recommended for the treatment of migraine of any severity in patients who have failed to gain adequate relief with nonspecific medication; early transition to triptans avoids prolonged morbidity in patients failing to respond to nonspecific medications. There is evidence that early intervention therapy with oral formulations in migraine, soon after the onset of an attack and when pain is still mild, improves efficacy. Seven different triptans are currently marketed, with differing pharmacologic, efficacy and tolerability profiles. Almotriptan has many positive features, which include rigorously demonstrated efficacy in sumatriptan nonresponders, as early therapy and in menstrual migraine. In addition, almotriptan has a favorable pharmacologic profile with a lack of clinically relevant pharmakinetic interventions with other drugs, adverse reactions rate similar to placebo, superior cost–effectiveness and excellent performance on composite clinical outcome measures that incorporate features of greatest importance to patients. Although effective in both triptan-naive and -experienced patients, and as both early and standard therapy, almotriptan shows greater efficacy in triptan-naive patients and as early treatment, and is consistently one of the preferred triptans in multiattribute decision-making analyses incorporating attributes of significance for patients and physicians. Therefore, almotriptan has many features that make it an ideal choice for a triptan-naive patient moving from nonspecific medication, a patient switching from another triptan owing to inefficacy or tolerability issues and patients being advised to take a triptan early in the course of a migraine attack.

When Basic Research Doesn't Translate to the Bedside—Lessons from the Magnesium Brain Trauma Study

Magnesium Sulfate for Neuroprotection After Traumatic Brain Injury: A Randomised Controlled Trial. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell DW, Mansfield PN, Machamer JE, Barber J, Dikmen SS. Lancet Neurol 2007;6(1):29–38. BACKGROUND: Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. METHODS: In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1 0–1·85 mmol/L or 1·25–2·5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with Clinicaltrials.gov, number NCT00004730. FINDINGS: Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean = 55 average percentile ranking on magnesium vs. 52 on placebo, 95% CI for difference – 7 to 14; p = 0·70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs. 54, 95% CI −10·5 to −2; p = 0007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. INTERPRETATION: Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

Crossing the Quality Chasm for Diabetes Care: The Power of One Physician, His Team, and Systems Thinking

To demonstrate that one physician can dramatically improve care of diabetes patients by taking a systems approach and getting support from leaders and other team members. Pre-/postcomparison of quality measures for the diabetes patients of one primary care physician, compared with those of his entire large multi-specialty medical group. Working with a mentor and with clinic and medical group leaders, he established a clear goal, focused on a repeatable and important performance measure, and used repeated rapid cycle trials to make systems changes in care, with extensive task delegation to team members and emphasis on repeated testing and treatment intensification. The composite outcome measure requires that each diabetes patient meet all 5 of the following: LDL <100, HbA(1C) <7, systolic blood pressure <130, regular aspirin use, and tobacco-free status. Over a 24-month period, quarterly measures for this physician's patients rose from 5.7% to 42.9%, while the 7000 diabetes patients of the entire medical group only increased from 4.2% to 12.1%. The change for those patients who stayed under his care for the entire period was even more dramatic-from 2.3% to 46.5% (P = <.0001). The largest improvements were for smoking documentation, aspirin use, and LDL control, with little change in HbA(1C) levels. One physician can accomplish a lot, if improvement is approached both systematically and persistently and if the work is coordinated with and supported by practice leaders.

Enzyme Replacement in Fabry Disease: The Essence Is in the Kidney

In this issue, Banikazemi and colleagues' landmark trial on Fabry disease provides a crucial path toward lowering the morbidity of this disease. Among other findings, they determined that hemizygou...

Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial

Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1.0-1.85 mmol/L or 1.25-2.5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with , number . Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference -7 to 14; p=0.70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI -10.5 to -2; p=0.007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.