Hamilton Health Sciences

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and is spread person-to-person through close contact. We aimed to investigate the effects of physical distance, face masks, and eye protection on virus transmission in health-care and non-health-care (eg, community) settings. METHODS: We did a systematic review and meta-analysis to investigate the optimum distance for avoiding person-to-person virus transmission and to assess the use of face masks and eye protection to prevent transmission of viruses. We obtained data for SARS-CoV-2 and the betacoronaviruses that cause severe acute respiratory syndrome, and Middle East respiratory syndrome from 21 standard WHO-specific and COVID-19-specific sources. We searched these data sources from database inception to May 3, 2020, with no restriction by language, for comparative studies and for contextual factors of acceptability, feasibility, resource use, and equity. We screened records, extracted data, and assessed risk of bias in duplicate. We did frequentist and Bayesian meta-analyses and random-effects meta-regressions. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. This study is registered with PROSPERO, CRD42020177047. FINDINGS: =0·090; posterior probability >95%, low certainty). Eye protection also was associated with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD -10·6%, 95% CI -12·5 to -7·7; low certainty). Unadjusted studies and subgroup and sensitivity analyses showed similar findings. INTERPRETATION: The findings of this systematic review and meta-analysis support physical distancing of 1 m or more and provide quantitative estimates for models and contact tracing to inform policy. Optimum use of face masks, respirators, and eye protection in public and health-care settings should be informed by these findings and contextual factors. Robust randomised trials are needed to better inform the evidence for these interventions, but this systematic appraisal of currently best available evidence might inform interim guidance. FUNDING: World Health Organization.

The Comprehensive Antibiotic Resistance Database (CARD; https://card.mcmaster.ca) is a curated resource providing reference DNA and protein sequences, detection models and bioinformatics tools on the molecular basis of bacterial antimicrobial resistance (AMR). CARD focuses on providing high-quality reference data and molecular sequences within a controlled vocabulary, the Antibiotic Resistance Ontology (ARO), designed by the CARD biocuration team to integrate with software development efforts for resistome analysis and prediction, such as CARD's Resistance Gene Identifier (RGI) software. Since 2017, CARD has expanded through extensive curation of reference sequences, revision of the ontological structure, curation of over 500 new AMR detection models, development of a new classification paradigm and expansion of analytical tools. Most notably, a new Resistomes & Variants module provides analysis and statistical summary of in silico predicted resistance variants from 82 pathogens and over 100 000 genomes. By adding these resistance variants to CARD, we are able to summarize predicted resistance using the information included in CARD, identify trends in AMR mobility and determine previously undescribed and novel resistance variants. Here, we describe updates and recent expansions to CARD and its biocuration process, including new resources for community biocuration of AMR molecular reference data.

BACKGROUND: Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. METHODS: Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). RESULTS: During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. CONCLUSIONS: In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

CONTEXT: Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. OBJECTIVE: To test the efficacy and safety of exercise training among patients with heart failure. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. INTERVENTIONS: Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. MAIN OUTCOME MEASURES: Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. RESULTS: The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. CONCLUSIONS: In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00047437.

IMPORTANCE: Hypertension is the most important preventable cause of morbidity and mortality globally, yet there are relatively few data collected using standardized methods. OBJECTIVE: To examine hypertension prevalence, awareness, treatment, and control in participants at baseline in the Prospective Urban Rural Epidemiology (PURE) study. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of 153,996 adults (complete data for this analysis on 142,042) aged 35 to 70 years, recruited between January 2003 and December 2009. Participants were from 628 communities in 3 high-income countries (HIC), 10 upper-middle-income and low-middle-income countries (UMIC and LMIC), and 4 low-income countries (LIC). MAIN OUTCOMES AND MEASURES: Hypertension was defined as individuals with self-reported treated hypertension or with an average of 2 blood pressure measurements of at least 140/90 mm Hg using an automated digital device. Awareness was based on self-reports, treatment was based on the regular use of blood pressure-lowering medications, and control was defined as individuals with blood pressure lower than 140/90 mm Hg. RESULTS: Among the 142,042 participants, 57,840 (40.8%; 95% CI, 40.5%-41.0%) had hypertension and 26,877 (46.5%; 95% CI, 46.1%-46.9%) were aware of the diagnosis. Of those who were aware of the diagnosis, the majority (23,510 [87.5%; 95% CI, 87.1%-87.9%] of those who were aware) were receiving pharmacological treatments, but only a minority of those receiving treatment were controlled (7634 [32.5%; 95% CI, 31.9%-33.1%]). Overall, 30.8%, 95% CI, 30.2%-31.4% of treated patients were taking 2 or more types of blood pressure-lowering medications. The percentages aware (49.0% [95% CI, 47.8%-50.3%] in HICs, 52.5% [95% CI, 51.8%-53.2%] in UMICs, 43.6% [95% CI, 42.9%-44.2%] in LMICs, and 40.8% [95% CI, 39.9%-41.8%] in LICs) and treated (46.7% [95% CI, 45.5%-47.9%] in HICs, 48.3%, [95% CI, 47.6%-49.1%] in UMICs, 36.9%, [95% CI, 36.3%-37.6%] in LMICs, and 31.7% [95% CI, 30.8%-32.6%] in LICs) were lower in LICs compared with all other countries for awareness (P <.001) and treatment (P <.001). Awareness, treatment, and control of hypertension were higher in urban communities compared with rural ones in LICs (urban vs rural, P <.001) and LMICs (urban vs rural, P <.001), but similar for other countries. Low education was associated with lower rates of awareness, treatment, and control in LICs, but not in other countries. CONCLUSIONS AND RELEVANCE: Among a multinational study population, 46.5% of participants with hypertension were aware of the diagnosis, with blood pressure control among 32.5% of those being treated. These findings suggest substantial room for improvement in hypertension diagnosis and treatment.

BACKGROUND: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. METHODS: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. RESULTS: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. CONCLUSIONS: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)

BACKGROUND: Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients. METHODS: We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure. RESULTS: We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001). CONCLUSIONS: Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).

BACKGROUND: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. METHODS: We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. RESULTS: Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). CONCLUSIONS: Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.).

BACKGROUND: The efficacy and safety of thromboprophylaxis in patients with acute medical illnesses who may be at risk for venous thromboembolism have not been determined in adequately designed trials. METHODS: In a double-blind study, we randomly assigned 1102 hospitalized patients older than 40 years to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days. Most patients were not in an intensive care unit. The primary outcome was venous thromboembolism between days 1 and 14, defined as deep-vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6 and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of follow-up was three months. RESULTS: The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant. CONCLUSIONS: Prophylactic treatment with 40 mg of enoxaparin subcutaneously per day safely and effectively reduces the risk of venous thromboembolism in patients with acute medical illnesses.

Severe acute respiratory syndrome (SARS) is a recently described illness of humans that has spread widely over the past 6 months. With the use of detailed epidemiologic data from Singapore and epidemic curves from other settings, we estimated the reproductive number for SARS in the absence of interventions and in the presence of control efforts. We estimate that a single infectious case of SARS will infect about three secondary cases in a population that has not yet instituted control measures. Public-health efforts to reduce transmission are expected to have a substantial impact on reducing the size of the epidemic.

BACKGROUND: Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. METHODS: In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. RESULTS: The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. CONCLUSIONS: The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).

IMPORTANCE: Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. OBJECTIVE: To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. EVIDENCE REVIEW: References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. RESULTS: Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. CONCLUSIONS AND RELEVANCE: Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

OBJECTIVE: To systematically review associations between intake of saturated fat and trans unsaturated fat and all cause mortality, cardiovascular disease (CVD) and associated mortality, coronary heart disease (CHD) and associated mortality, ischemic stroke, and type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Central Registry of Controlled Trials, Evidence-Based Medicine Reviews, and CINAHL from inception to 1 May 2015, supplemented by bibliographies of retrieved articles and previous reviews. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Observational studies reporting associations of saturated fat and/or trans unsaturated fat (total, industrially manufactured, or from ruminant animals) with all cause mortality, CHD/CVD mortality, total CHD, ischemic stroke, or type 2 diabetes. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data and assessed study risks of bias. Multivariable relative risks were pooled. Heterogeneity was assessed and quantified. Potential publication bias was assessed and subgroup analyses were undertaken. The GRADE approach was used to evaluate quality of evidence and certainty of conclusions. RESULTS: For saturated fat, three to 12 prospective cohort studies for each association were pooled (five to 17 comparisons with 90,501-339,090 participants). Saturated fat intake was not associated with all cause mortality (relative risk 0.99, 95% confidence interval 0.91 to 1.09), CVD mortality (0.97, 0.84 to 1.12), total CHD (1.06, 0.95 to 1.17), ischemic stroke (1.02, 0.90 to 1.15), or type 2 diabetes (0.95, 0.88 to 1.03). There was no convincing lack of association between saturated fat and CHD mortality (1.15, 0.97 to 1.36; P=0.10). For trans fats, one to six prospective cohort studies for each association were pooled (two to seven comparisons with 12,942-230,135 participants). Total trans fat intake was associated with all cause mortality (1.34, 1.16 to 1.56), CHD mortality (1.28, 1.09 to 1.50), and total CHD (1.21, 1.10 to 1.33) but not ischemic stroke (1.07, 0.88 to 1.28) or type 2 diabetes (1.10, 0.95 to 1.27). Industrial, but not ruminant, trans fats were associated with CHD mortality (1.18 (1.04 to 1.33) v 1.01 (0.71 to 1.43)) and CHD (1.42 (1.05 to 1.92) v 0.93 (0.73 to 1.18)). Ruminant trans-palmitoleic acid was inversely associated with type 2 diabetes (0.58, 0.46 to 0.74). The certainty of associations between saturated fat and all outcomes was "very low." The certainty of associations of trans fat with CHD outcomes was "moderate" and "very low" to "low" for other associations. CONCLUSIONS: Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations. Trans fats are associated with all cause mortality, total CHD, and CHD mortality, probably because of higher levels of intake of industrial trans fats than ruminant trans fats. Dietary guidelines must carefully consider the health effects of recommendations for alternative macronutrients to replace trans fats and saturated fats.

BACKGROUND: Although a wealth of literature links dietary factors and coronary heart disease (CHD), the strength of the evidence supporting valid associations has not been evaluated systematically in a single investigation. METHODS: We conducted a systematic search of MEDLINE for prospective cohort studies or randomized trials investigating dietary exposures in relation to CHD. We used the Bradford Hill guidelines to derive a causation score based on 4 criteria (strength, consistency, temporality, and coherence) for each dietary exposure in cohort studies and examined for consistency with the findings of randomized trials. RESULTS: Strong evidence supports valid associations (4 criteria satisfied) of protective factors, including intake of vegetables, nuts, and "Mediterranean" and high-quality dietary patterns with CHD, and associations of harmful factors, including intake of trans-fatty acids and foods with a high glycemic index or load. Among studies of higher methodologic quality, there was also strong evidence for monounsaturated fatty acids and "prudent" and "western" dietary patterns. Moderate evidence (3 criteria) of associations exists for intake of fish, marine omega-3 fatty acids, folate, whole grains, dietary vitamins E and C, beta carotene, alcohol, fruit, and fiber. Insufficient evidence (< or =2 criteria) of association is present for intake of supplementary vitamin E and ascorbic acid (vitamin C); saturated and polyunsaturated fatty acids; total fat; alpha-linolenic acid; meat; eggs; and milk. Among the dietary exposures with strong evidence of causation from cohort studies, only a Mediterranean dietary pattern is related to CHD in randomized trials. CONCLUSIONS: The evidence supports a valid association of a limited number of dietary factors and dietary patterns with CHD. Future evaluation of dietary patterns, including their nutrient and food components, in cohort studies and randomized trials is recommended.

CONTEXT: Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. OBJECTIVE: To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. INTERVENTION: Daily dose of natural source vitamin E (400 IU) or matching placebo. MAIN OUTCOME MEASURES: Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. RESULTS: Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. CONCLUSION: In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.

BACKGROUND: Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS: In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS: The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS: Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

CONTEXT: Low adherence with prescribed treatments is ubiquitous and undermines treatment benefits. OBJECTIVE: To systematically review published randomized controlled trials (RCTs) of interventions to assist patients' adherence to prescribed medications. DATA SOURCES: A search of MEDLINE, CINAHL, PSYCHLIT, SOCIOFILE, IPA, EMBASE, The Cochrane Library databases, and bibliographies was performed for records from 1967 through August 2001 to identify relevant articles of all RCTs of interventions intended to improve adherence to self-administered medications. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they reported an unconfounded RCT of an intervention to improve adherence with prescribed medications for a medical or psychiatric disorder; both adherence and treatment outcome were measured; follow-up of at least 80% of each study group was reported; and the duration of follow-up for studies with positive initial findings was at least 6 months. Information on study design features, interventions, controls, and findings (adherence rates and patient outcomes) were extracted for each article. DATA SYNTHESIS: Studies were too disparate to warrant meta-analysis. Forty-nine percent of the interventions tested (19 of 39 in 33 studies) were associated with statistically significant increases in medication adherence and only 17 reported statistically significant improvements in treatment outcomes. Almost all the interventions that were effective for long-term care were complex, including combinations of more convenient care, information, counseling, reminders, self-monitoring, reinforcement, family therapy, and other forms of additional supervision or attention. Even the most effective interventions had modest effects. CONCLUSIONS: Current methods of improving medication adherence for chronic health problems are mostly complex, labor-intensive, and not predictably effective. The full benefits of medications cannot be realized at currently achievable levels of adherence; therefore, more studies of innovative approaches to assist patients to follow prescriptions for medications are needed.