Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10.

BMJ. 2012;344:e2990

Authors: Lidegaard O, Nielsen LH, Skovlund CW, Løkkegaard E

Abstract
OBJECTIVE: To assess the risk of venous thrombosis in current users of non-oral hormonal contraception.
DESIGN: Historical national registry based cohort study.
SETTING: Four national registries in Denmark.
PARTICIPANTS: All Danish non-pregnant women aged 15-49 (n=1?626?158), free of previous thrombotic disease or cancer, were followed from 2001 to 2010.
MAIN OUTCOME MEASURES: Incidence rate of venous thrombosis in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception, relative risk of venous thrombosis compared with non-users, and rate ratios of venous thrombosis in current users of non-oral products compared with the standard reference oral contraceptive with levonorgestrel and 30-40 µg oestrogen. Diagnoses were confirmed by at least four weeks of anticoagulation therapy after the diagnosis.
RESULTS: Within 9?429?128 woman years of observation, 5287 first ever venous thrombosis events were recorded, of which 3434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10?000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10?000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7).
CONCLUSION: Women who use transdermal patches or vaginal rings for contraception have a 7.9 and 6.5 times increased risk of confirmed venous thrombosis compared with non-users of hormonal contraception of the same age, corresponding to 9.7 and 7.8 events per 10?000 exposure years. The risk was slightly increased in women using subcutaneous implants but not in those using the levonorgestrel intrauterine system.

PMID: 22577198 [PubMed - in process]

Evaluation of the national Cleanyourhands campaign to reduce Staphylococcus aureus bacteraemia and Clostridium difficile infection in hospitals in England and Wales by improved hand hygiene: four year, prospective, ecological, interrupted time series study.

BMJ. 2012;344:e3005

Authors: Stone SP, Fuller C, Savage J, Cookson B, Hayward A, Cooper B, Duckworth G, Michie S, Murray M, Jeanes A, Roberts J, Teare L, Charlett A

Abstract
OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement.
DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008.
SETTING: 187 acute trusts in England and Wales.
INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004.
MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections).
RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10?000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P<0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P<0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P=0.02) and C difficile infection (0.75, 0.67 to 0.84; P<0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit.
CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.

PMID: 22556101 [PubMed - in process]

Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

BMJ. 2012;344:e1771

Authors: Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, Almdal T

Abstract
OBJECTIVES: To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes.
DESIGN: Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.
DATA SOURCES: The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website.
REVIEW METHODS: Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes.
RESULTS: We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA(1c), weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA(1c) reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day.
CONCLUSIONS: There was no evidence or even a trend towards improved all cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes. Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control.

PMID: 22517929 [PubMed - in process]

Patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in 12 countries in Europe and the United States.

BMJ. 2012;344:e1717

Authors: Aiken LH, Sermeus W, Van den Heede K, Sloane DM, Busse R, McKee M, Bruyneel L, Rafferty AM, Griffiths P, Moreno-Casbas MT, Tishelman C, Scott A, Brzostek T, Kinnunen J, Schwendimann R, Heinen M, Zikos D, Sjetne IS, Smith HL, Kutney-Lee A

Abstract
OBJECTIVE: To determine whether hospitals with a good organisation of care (such as improved nurse staffing and work environments) can affect patient care and nurse workforce stability in European countries.
DESIGN: Cross sectional surveys of patients and nurses.
SETTING: Nurses were surveyed in general acute care hospitals (488 in 12 European countries; 617 in the United States); patients were surveyed in 210 European hospitals and 430 US hospitals.
PARTICIPANTS: 33?659 nurses and 11?318 patients in Europe; 27?509 nurses and more than 120?000 patients in the US.
MAIN OUTCOME MEASURES: Nurse outcomes (hospital staffing, work environments, burnout, dissatisfaction, intention to leave job in the next year, patient safety, quality of care), patient outcomes (satisfaction overall and with nursing care, willingness to recommend hospitals).
RESULTS: The percentage of nurses reporting poor or fair quality of patient care varied substantially by country (from 11% (Ireland) to 47% (Greece)), as did rates for nurses who gave their hospital a poor or failing safety grade (4% (Switzerland) to 18% (Poland)). We found high rates of nurse burnout (10% (Netherlands) to 78% (Greece)), job dissatisfaction (11% (Netherlands) to 56% (Greece)), and intention to leave (14% (US) to 49% (Finland, Greece)). Patients' high ratings of their hospitals also varied considerably (35% (Spain) to 61% (Finland, Ireland)), as did rates of patients willing to recommend their hospital (53% (Greece) to 78% (Switzerland)). Improved work environments and reduced ratios of patients to nurses were associated with increased care quality and patient satisfaction. In European hospitals, after adjusting for hospital and nurse characteristics, nurses with better work environments were half as likely to report poor or fair care quality (adjusted odds ratio 0.56, 95% confidence interval 0.51 to 0.61) and give their hospitals poor or failing grades on patient safety (0.50, 0.44 to 0.56). Each additional patient per nurse increased the odds of nurses reporting poor or fair quality care (1.11, 1.07 to 1.15) and poor or failing safety grades (1.10, 1.05 to 1.16). Patients in hospitals with better work environments were more likely to rate their hospital highly (1.16, 1.03 to 1.32) and recommend their hospitals (1.20, 1.05 to 1.37), whereas those with higher ratios of patients to nurses were less likely to rate them highly (0.94, 0.91 to 0.97) or recommend them (0.95, 0.91 to 0.98). Results were similar in the US. Nurses and patients agreed on which hospitals provided good care and could be recommended.
CONCLUSIONS: Deficits in hospital care quality were common in all countries. Improvement of hospital work environments might be a relatively low cost strategy to improve safety and quality in hospital care and to increase patient satisfaction.

PMID: 22434089 [PubMed - in process]

Meta-analysis of individual patient data in randomised trials of self monitoring of blood glucose in people with non-insulin treated type 2 diabetes.

BMJ. 2012;344:e486

Authors: Farmer AJ, Perera R, Ward A, Heneghan C, Oke J, Barnett AH, Davidson MB, Guerci B, Coates V, Schwedes U, O'Malley S

Abstract
OBJECTIVE: To assess the effectiveness of self monitoring blood glucose levels in people with non-insulin treated type 2 diabetes compared with clinical management without self monitoring, and to explore the effects in specific patient groups.
DESIGN: Meta-analysis based on individual participant data.
DATA SOURCES: Medline, Embase, and a recent systematic review of trials on self monitoring of blood glucose. Chief investigators of trials published since 2000 were approached for additional information and individual patient data.
INCLUSION CRITERIA: Randomised controlled trials in patients with non-insulin treated type 2 diabetes comparing an intervention using self monitoring of blood glucose with clinical management not using self monitoring. Trials published from 2000 with at least 80 participants were included. DATA COLLECTION : Individual patient data were collected from electronic files and checked for integrity.
ANALYSIS: All randomised participants were analysed using the intention to treat principle. A random effects model of complete cases was used to assess efficacy, a sensitivity analysis comprised imputed data, and prespecified subgroup analyses were carried out for age, sex, previous use of self monitoring, duration of diabetes, and levels of glycated haemoglobin (HbA(1c)) at baseline.
RESULTS: 2552 patients were randomised in the six included trials. A mean reduction in HbA(1c) level of -2.7 mmol/mol (95% confidence interval -3.9 to -1.6; 0.25%) was observed for those using self monitoring of blood glucose levels compared with no self monitoring at six months. The mean reduction in HbA(1c) level between groups was 2.0 mmol/mol (3.2 to 0.8; 0.25%) at three months (five trials) and 2.5 mmol/mol (4.1 to 0.9; 0.35%) at 12 months (three trials). These estimates were unchanged after imputing missing data, and estimates of effect in trials with higher loss to follow-up or a possibility of co-intervention compared with those with lower loss to follow-up and no co-intervention did not differ significantly (P=0.21). The difference in HbA(1c) levels between groups was consistent across age, baseline HbA(1c) level, sex, and duration of diabetes, although the numbers of older and younger people and those with HbA(1c) levels >86 mmol/mol (10%) were insufficient for interpretation. No changes occurred in systolic blood pressure (-0.2 mm Hg, 95% confidence interval -1.4 to 1.0), diastolic blood pressure (-0.1 mm Hg, -0.9 to 0.6), or total cholesterol level (-0.1 mol/L, 95% confidence interval -0.2 to 0.1).
CONCLUSIONS: Evidence from this meta-analysis of individual patient data was not convincing for a clinically meaningful effect of clinical management of non-insulin treated type 2 diabetes by self monitoring of blood glucose levels compared with management without self monitoring, although the difference in HbA(1c) level between groups was statistically significant. The difference in levels was consistent across subgroups defined by personal and clinical characteristics.

PMID: 22371867 [PubMed - in process]

Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study.

BMJ. 2011;343:d6829

Authors: Tzoulaki I, Siontis KC, Ioannidis JP

Abstract
OBJECTIVE: To compare the reported effect sizes of cardiovascular biomarkers in datasets from observational studies with those in datasets from randomised controlled trials.
DESIGN: Review of meta-analyses.
STUDY SELECTION: Meta-analyses of emerging cardiovascular biomarkers (not part of the Framingham risk score) that included datasets from at least one observational study and at least one randomised controlled trial were identified through Medline (last update, January 2011).
DATA EXTRACTION: Study-specific risk ratios were extracted from all identified meta-analyses and synthesised with random effects for (a) all studies, and (b) separately for observational and for randomised controlled trial populations for comparison.
RESULTS: 31 eligible meta-analyses were identified. For seven major biomarkers (C reactive protein, non-HDL cholesterol, lipoprotein(a), post-load glucose, fibrinogen, B-type natriuretic peptide, and troponins), the prognostic effect was significantly stronger in datasets from observational studies than in datasets from randomised controlled trials. For five of the biomarkers the effect was less than half as strong in the randomised controlled trial datasets. Across all 31 meta-analyses, on average datasets from observational studies suggested larger prognostic effects than those from randomised controlled trials; from a random effects meta-analysis, the estimated average difference in the effect size was 24% (95% CI 7% to 40%) of the overall biomarker effect.
CONCLUSIONS: Cardiovascular biomarkers often have less promising results in the evidence derived from randomised controlled trials than from observational studies.

PMID: 22065657 [PubMed - indexed for MEDLINE]

Comprehensive geriatric assessment for older adults admitted to hospital: meta-analysis of randomised controlled trials.

BMJ. 2011;343:d6553

Authors: Ellis G, Whitehead MA, Robinson D, O'Neill D, Langhorne P

Abstract
OBJECTIVE: To evaluate the effectiveness of comprehensive geriatric assessment in hospital for older adults admitted as an emergency.
SEARCH STRATEGY: We searched the EPOC Register, Cochrane's Controlled Trials Register, the Database of Abstracts of Reviews of Effects (DARE), Medline, Embase, CINAHL, AARP Ageline, and handsearched high yield journals.
SELECTION CRITERIA: Randomised controlled trials of comprehensive geriatric assessment (whether by mobile teams or in designated wards) compared with usual care. Comprehensive geriatric assessment is a multidimensional interdisciplinary diagnostic process used to determine the medical, psychological, and functional capabilities of a frail elderly person to develop a coordinated and integrated plan for treatment and long term follow-up.
DATA COLLECTION AND ANALYSIS: Three independent reviewers assessed eligibility and trial quality and extracted published data. Two additional reviewers moderated.
RESULTS: Twenty two trials evaluating 10,315 participants in six countries were identified. For the primary outcome "living at home," patients who underwent comprehensive geriatric assessment were more likely to be alive and in their own homes at the end of scheduled follow-up (odds ratio 1.16 (95% confidence interval 1.05 to 1.28; P = 0.003; number needed to treat 33) at a median follow-up of 12 months versus 1.25 (1.11 to 1.42; P < 0.001; number needed to treat 17) at a median follow-up of six months) compared with patients who received general medical care. In addition, patients were less likely to be living in residential care (0.78, 0.69 to 0.88; P < 0.001). Subgroup interaction suggested differences between the subgroups "wards" and "teams" in favour of wards. Patients were also less likely to die or experience deterioration (0.76, 0.64 to 0.90; P = 0.001) and were more likely to experience improved cognition (standardised mean difference 0.08, 0.01 to 0.15; P = 0.02) in the comprehensive geriatric assessment group.
CONCLUSIONS: Comprehensive geriatric assessment increases patients' likelihood of being alive and in their own homes after an emergency admission to hospital. This seems to be especially true for trials of wards designated for comprehensive geriatric assessment and is associated with a potential cost reduction compared with general medical care.

PMID: 22034146 [PubMed - indexed for MEDLINE]

Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials.

BMJ. 2011;343:d6898

Authors: Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal T, Hemmingsen C, Wetterslev J

Abstract
Objective To assess the effect of targeting intensive glycaemic control versus conventional glycaemic control on all cause mortality and cardiovascular mortality, non-fatal myocardial infarction, microvascular complications, and severe hypoglycaemia in patients with type 2 diabetes. Design Systematic review with meta-analyses and trial sequential analyses of randomised trials. Data sources Cochrane Library, Medline, Embase, Science Citation Index Expanded, LILACS, and CINAHL to December 2010; hand search of reference lists and conference proceedings; contacts with authors, relevant pharmaceutical companies, and the US Food and Drug Administration. Study selection Randomised clinical trials comparing targeted intensive glycaemic control with conventional glycaemic control in patients with type 2 diabetes. Published and unpublished trials in all languages were included, irrespective of predefined outcomes. Data extraction Two reviewers independently assessed studies for inclusion and extracted data related to study methods, interventions, outcomes, risk of bias, and adverse events. Risk ratios with 95% confidence intervals were estimated with fixed and random effects models. Results Fourteen clinical trials that randomised 28?614 participants with type 2 diabetes (15?269 to intensive control and 13?345 to conventional control) were included. Intensive glycaemic control did not significantly affect the relative risks of all cause (1.02, 95% confidence interval 0.91 to 1.13; 28?359 participants, 12 trials) or cardiovascular mortality (1.11, 0.92 to 1.35; 28?359 participants, 12 trials). Trial sequential analyses rejected a relative risk reduction above 10% for all cause mortality and showed insufficient data on cardiovascular mortality. The risk of non-fatal myocardial infarction may be reduced (relative risk 0.85, 0.76 to 0.95; P=0.004; 28?111 participants, 8 trials), but this finding was not confirmed in trial sequential analysis. Intensive glycaemic control showed a reduction of the relative risks for the composite microvascular outcome (0.88, 0.79 to 0.97; P=0.01; 25?600 participants, 3 trials) and retinopathy (0.80, 0.67 to 0.94; P=0.009; 10?793 participants, 7 trials), but trial sequential analyses showed that sufficient evidence had not yet been reached. The estimate of an effect on the risk of nephropathy (relative risk 0.83, 0.64 to 1.06; 27?769 participants, 8 trials) was not statistically significant. The risk of severe hypoglycaemia was significantly increased when intensive glycaemic control was targeted (relative risk 2.39, 1.71 to 3.34; 27?844 participants, 9 trials); trial sequential analysis supported a 30% increased relative risk of severe hypoglycaemia. CONCLUSION: Intensive glycaemic control does not seem to reduce all cause mortality in patients with type 2 diabetes. Data available from randomised clinical trials remain insufficient to prove or refute a relative risk reduction for cardiovascular mortality, non-fatal myocardial infarction, composite microvascular complications, or retinopathy at a magnitude of 10%. Intensive glycaemic control increases the relative risk of severe hypoglycaemia by 30%.

PMID: 22115901 [PubMed - in process]

Association of echocardiography before major elective non-cardiac surgery with postoperative survival and length of hospital stay: population based cohort study.

BMJ. 2011;342:d3695

Authors: Wijeysundera DN, Beattie WS, Karkouti K, Neuman MD, Austin PC, Laupacis A

Abstract
OBJECTIVE: To determine the association of resting echocardiography before elective intermediate to high risk non-cardiac surgery with survival and length of hospital stay.
DESIGN: Population based retrospective cohort study.
SETTING: Acute care hospitals in Ontario, Canada, between 1 April 1999 and 31 March 2008.
PARTICIPANTS: Patients aged over 40 years who had elective intermediate to high risk non-cardiac surgery.
INTERVENTION: Resting echocardiography within 6 months before surgery.
MAIN OUTCOME MEASURES: Postoperative survival (30 days and 1 year) and length of hospital stay; postoperative surgical site infection as an outcome for which no association with echocardiography would be expected.
RESULTS: Of the 264,823 patients in the entire cohort, 15.1% (n = 40,084) had echocardiography. After use of propensity score methods to assemble a matched cohort (n = 70,996) that reduced differences between patients who had or had not had echocardiography, echocardiography was associated with increases in 30 day mortality (relative risk 1.14, 95% confidence interval 1.02 to 1.27), 1 year mortality (1.07, 1.01 to 1.12), and length of hospital stay but no difference in surgical site infections (1.03, 0.98 to 1.06). The association with mortality was influenced (P = 0.02) by whether patients had had stress testing or had risk factors for cardiac complications. No association existed between echocardiography and mortality among patients who had stress testing (relative risk 1.01, 0.92 to 1.11) or among patients at high risk who had not had stress testing (1.00, 0.87 to 1.13). However, echocardiography was associated with mortality in patients at low risk (relative risk 1.44, 1.14 to 1.82) and intermediate risk (1.10, 1.02 to 1.18) who had not had stress testing.
CONCLUSIONS: Preoperative echocardiography was not associated with improved survival or shorter hospital stay after major non-cardiac surgery. These findings highlight the need for further research to guide better use of this common preoperative test.

PMID: 21724560 [PubMed - indexed for MEDLINE]

Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.

BMJ. 2011;342:d3527

Authors: James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, Katus H, Morais J, Steg PG, Storey RF, Stevens S, Wallentin L, Harrington RA,

Abstract
OBJECTIVE: To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.
DESIGN: Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.
SETTING: 862 centres in 43 countries.
PARTICIPANTS: 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.
INTERVENTIONS: Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).
MAIN OUTCOME MEASUREMENTS: Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.
RESULTS: 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.
CONCLUSIONS: In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.
TRIAL REGISTRATION: Clinical trials NCT00391872.

PMID: 21685437 [PubMed - indexed for MEDLINE]

Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.

BMJ. 2011;342:d3215

Authors: Singh S, Loke YK, Enright PL, Furberg CD

Abstract
OBJECTIVE: To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.
DATA SOURCES: Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.
STUDY SELECTION: Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic.
RESULTS: Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 µg (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 µg (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.
CONCLUSIONS: This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.

PMID: 21672999 [PubMed - indexed for MEDLINE]

Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial.

BMJ. 2011;342:d3653

Authors: Hobbs FD, Roalfe AK, Lip GY, Fletcher K, Fitzmaurice DA, Mant J,

Abstract
OBJECTIVE: To compare the predictive power of the main existing and recently proposed schemes for stratification of risk of stroke in older patients with atrial fibrillation.
DESIGN: Comparative cohort study of eight risk stratification scores.
SETTING: Trial of thromboprophylaxis in stroke, the Birmingham Atrial Fibrillation in the Aged (BAFTA) trial.
PARTICIPANTS: 665 patients aged 75 or over with atrial fibrillation based in the community who were randomised to the BAFTA trial and were not taking warfarin throughout or for part of the study period.
MAIN OUTCOME MEASURES: Events rates of stroke and thromboembolism.
RESULTS: 54 (8%) patients had an ischaemic stroke, four (0.6%) had a systemic embolism, and 13 (2%) had a transient ischaemic attack. The distribution of patients classified into the three risk categories (low, moderate, high) was similar across three of the risk stratification scores (revised CHADS(2), NICE, ACC/AHA/ESC), with most patients categorised as high risk (65-69%, n = 460-457) and the remaining classified as moderate risk. The original CHADS(2) (Congestive heart failure, Hypertension, Age ? 75 years, Diabetes, previous Stroke) score identified the lowest number as high risk (27%, n = 180). The incremental risk scores of CHADS(2), Rietbrock modified CHADS(2), and CHA(2)DS(2)-VASc (CHA(2)DS(2)-Vascular disease, Age 65-74 years, Sex) failed to show an increase in risk at the upper range of scores. The predictive accuracy was similar across the tested schemes with C statistic ranging from 0.55 (original CHADS(2)) to 0.62 (Rietbrock modified CHADS(2)), with all except the original CHADS(2) predicting better than chance. Bootstrapped paired comparisons provided no evidence of significant differences between the discriminatory ability of the schemes.
CONCLUSIONS: Based on this single trial population, current risk stratification schemes in older people with atrial fibrillation have only limited ability to predict the risk of stroke. Given the systematic undertreatment of older people with anticoagulation, and the relative safety of warfarin versus aspirin in those aged over 70, there could be a pragmatic rationale for classifying all patients over 75 as "high risk" until better tools are available.

PMID: 21700651 [PubMed - indexed for MEDLINE]

Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses.

BMJ. 2011;343:d6333

Authors: Pink J, Lane S, Pirmohamed M, Hughes DA

Abstract
OBJECTIVES: To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.
DESIGN: Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.
SETTING: UK National Health Service. Population Cohorts of 50?000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS(2) (Congestive heart failure, Hypertension, Age?75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.
MAIN OUTCOME MEASURES: Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.
RESULTS: Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range -0.083 to 0.267) and 0.146 (-0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23?082 (€26?700; $35?800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS(2) score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42?386 per QALY gained.
CONCLUSIONS: This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.

PMID: 22042753 [PubMed - in process]

Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.

BMJ. 2011;343:d5228

Authors: Antoniou T, Gomes T, Mamdani MM, Yao Z, Hellings C, Garg AX, Weir MA, Juurlink DN

Abstract
OBJECTIVES: To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone.
DESIGN: Population based nested case-control study.
SETTING: Ontario, Canada, from 1 April 1992 to 1 March 2010.
PARTICIPANTS: Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case's index date.
MAIN OUTCOME MEASURES: Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia.
RESULTS: During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17?859/165?754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of hyperkalaemia (adjusted odds ratio 2.4, 1.3 to 4.6), but no such risk was found with norfloxacin (adjusted odds ratio 1.6, 0.8 to 3.4)
CONCLUSIONS: Among older patients receiving spironolactone, treatment with trimethoprim-sulfamethoxazole was associated with a major increase in the risk of admission to hospital for hyperkalaemia. This drug combination should be avoided when possible.

PMID: 21911446 [PubMed - in process]

Development and validation of risk prediction algorithm (QThrombosis) to estimate future risk of venous thromboembolism: prospective cohort study.

BMJ. 2011;343:d4656

Authors: Hippisley-Cox J, Coupland C

Abstract
OBJECTIVES: To derive and validate a new clinical risk prediction algorithm (QThrombosis, www.qthrombosis.org) to estimate individual patients' risk of venous thromboembolism.
DESIGN: Prospective open cohort study using routinely collected data from general practices. Cox proportional hazards models used in derivation cohort to derive risk equations evaluated at 1 and 5 years. Measures of calibration and discrimination undertaken in validation cohort.
SETTING: 564 general practices in England and Wales contributing to the QResearch database.
PARTICIPANTS: Patients aged 25-84 years, with no record of pregnancy in the preceding 12 months or any previous venous thromboembolism, and not prescribed oral anticoagulation at baseline: 2?314?701 in derivation cohort and 1?240?602 in validation cohort. Outcomes Incident cases of venous thromboembolism, either deep vein thrombosis or pulmonary embolism, recorded in primary care records or linked cause of death records.
RESULTS: The derivation cohort included 14?756 incident cases of venous thromboembolism from 10?095?199 person years of observation (rate of 14.6 per 10?000 person years). The validation cohort included 6913 incident cases from 4?632?694 person years of observation (14.9 per 10?000 person years). Independent predictors included in the final model for men and women were age, body mass index, smoking status, varicose veins, congestive cardiac failure, chronic renal disease, cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, hospital admission in past six months, and current prescriptions for antipsychotic drugs. We also included oral contraceptives, tamoxifen, and hormone replacement therapy in the final model for women. The risk prediction equation explained 33% of the variation in women and 34% in men in the validation cohort evaluated at 5 years The D statistic was 1.43 for women and 1.45 for men. The receiver operating curve statistic was 0.75 for both sexes. The model was well calibrated.
CONCLUSIONS: We have developed and validated a new risk prediction model that quantifies absolute risk of thrombosis at 1 and 5 years. It can help identify patients at high risk of venous thromboembolism for prevention. The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records. The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism.

PMID: 21846713 [PubMed - in process]