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1.  Thanks to all those who reviewed for Trials in 2014 
Trials  2015;16:55.
Contributing reviewers
A peer-reviewed journal would not survive without the generous time and insightful comments of the reviewers, whose efforts often go unrecognized. Although final decisions are always editorial, they are greatly facilitated by the deeper technical knowledge, scientific insights, understanding of social consequences, and passion that reviewers bring to our deliberations. For these reasons, the Editors-in-Chief and staff of the journal warmly thank the 610 reviewers whose comments helped to shape Trials, for their invaluable assistance with review of manuscripts for the journal in Volume 15 (2014).
PMCID: PMC4336513
2.  Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE-Inhibitor, or Calcium-Channel Blocker in ALLHAT 
Calcium channel-blockers (CCB) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal hemorrhage. Using administrative databases, we re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the calcium-channel blocker amlodipine had a greater risk of hospitalized gastrointestinal bleeding (a pre-specified outcome) compared to those randomized to the diuretic chlorthalidone or the ACE-inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for gastrointestinal bleeding hospitalizations compared to participants randomized to amlodipine (HR, 1.09, 95% CI 0.92-1.28). Those randomized to lisinopril were at increased risk of gastrointestinal bleeding compared those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned lisinopril therapy had a higher risk of hospitalized gastrointestinal hemorrhage (HR,1.27, 95% CI 1.06-1.51) versus those assigned to amlodipine. In-study use of atenolol prior to first gastrointestinal hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). In conclusion, hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared to those on either chlorthalidone or lisinopril.
PMCID: PMC3844932  PMID: 24283598
3.  Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) and Risk of Cardiovascular Disease in Older Adults: Results from the Cardiovascular Health Study 
Atherosclerosis  2009;209(2):528-532.
To examine associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults.
We examined associations of Lp-PLA2 mass and activity with incident myocardial infarction (MI; n=508), stroke (n= 565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3,949 older adults, aged ≥ 65 years at baseline, from the Cardiovascular Health Study (CHS).
Lp-PLA2 was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA2 mass were 1.49 (1.19–1.85) for MI, 1.21 (0.98–1.49) for stroke and 1.11 (0.92–1.33) for CVD death. The highest tertile of Lp-PLA2 activity was associated with MI (1.36; 1.09–1.70) and CVD death (1.23; 1.02–1.50). Combined Lp-PLA2 tertile 3 and CRP >3mg/l, compared to Lp-PLA2 tertile 1 and CRP <1 mg/l, was associated with MI (2.29; 1.49–3.52) for Lp-PLA2 mass and MI (1.66; 1.10–2.51) and CVD death (1.57; 1.08–2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone (~20% excess risk) and activity added excess risk for CVD death (~12%).
Lp-PLA2 mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA2 and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA2 to identify older individuals at risk for CVD.
PMCID: PMC2846186  PMID: 19804884
Epidemiology; Inflammation; Cardiovascular diseases; Lipoprotein-associated phospholipase A2
4.  Linked publications from a single trial: a thread of evidence 
Trials  2014;15(1):369.
PMCID: PMC4183771  PMID: 25248292
5.  Antihypertensive drugs decrease risk of Alzheimer disease 
Neurology  2013;81(10):896-903.
The aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or β-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI).
Secondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n = 1,928) or MCI (n = 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders.
Diuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31–0.82), 0.31 in ARB (95% CI 0.14–0.68), 0.50 in ACE-I (95% CI 0.29–0.83), 0.62 in CCB (95% CI 0.35–1.09), and 0.58 in BB (95% CI 0.36–0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio = 0.38, 95% CI 0.20–0.73).
Diuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI.
PMCID: PMC3885216  PMID: 23911756
6.  Mortality and morbidity during and after ALLHAT: Results by gender 
Hypertension  2013;61(5):977-986.
To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in gender subgroups, we carried out a prespecified subgroup analysis of 15,638 female and 17,719 male participants in the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure, or peripheral vascular disease), and end-stage renal disease. In-trial rates of heart failure, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared to chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared to chlorthalidone in both men and women. There were no significant treatment gender interactions. These findings did not persist through the extension period with the exception of the heart failure result for amlodipine versus chlorthalidone, which did not differ significantly by gender. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of heart failure. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men.
PMCID: PMC4114223  PMID: 23529173
hypertension; gender; diuretic; calcium channel blocker; ACE inhibitor
7.  To whom do the research findings apply? 
Heart  2002;87(6):570-574.
PMCID: PMC1767149  PMID: 12010948
clinical research; drug trials
8.  Relations of Change in Plasma Levels of LDL‐C, Non‐HDL‐C and apoB With Risk Reduction From Statin Therapy: A Meta‐Analysis of Randomized Trials 
Identifying the best markers to judge the adequacy of lipid‐lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid‐lowering therapies are in development. Reductions in LDL‐C, non‐HDL‐C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established.
Methods and Results
We performed a random‐effects frequentist and Bayesian meta‐analysis of 7 placebo‐controlled statin trials in which LDL‐C, non‐HDL‐C, and apoB values were available at baseline and at 1‐year follow‐up. Summary level data for change in LDL‐C, non‐HDL‐C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta‐analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL‐C; 20.0% (15.2%, 24.7%) for non‐HDL‐C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL‐C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non‐HDL‐C (P<0.001). Similarly, in Bayesian meta‐analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL‐C or non‐HDL‐C (BFs ranging from 484 to 2380).
Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo‐controlled statin trials was more closely related to reductions in apoB than to reductions in either non‐HDL‐C or LDL‐C.
PMCID: PMC4187506  PMID: 24732920
apoB; LDL‐C; meta‐analysis; non‐HDL‐C; statins
9.  Midcourse correction to a clinical trial when the event rate is underestimated: the Look AHEAD (Action for Health in Diabetes) Study 
The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up.
The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues.
The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power.
Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.
PMCID: PMC3790961  PMID: 22334468
Hypertension  2012;59(5):926-933.
Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. ALLHAT, a large practice-based clinical trial made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone versus amlodipine or lisinopril as first-step drug were stratified by year-1 potassium. Post-year-1 outcomes among hypokalemics (potassium<3.5mmol/L) and hyperkalemics (potassium>5.4mmol/L) were compared to normokalemics (potassium 3.5–5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in chlorthalidone (12.9%) differed from amlodipine (2.1%; p<0.001) and lisinopril (1.0%; p<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than chlorthalidone (1.2%; p<0.01) or amlodipine (1.9%; p<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than normokalemics (Cox hazard ratio =1.21; 95% confidence interval=1.02–1.44) with statistically significant (interaction p<0.01) disparity in hazard ratios for the three treatment arms (hazard ratios: chlorthalidone=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio=1.58; 1.15–2.18) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of chlorthalidone. Thus, for most patients, concerns about potassium levels should not influence clinician’s decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5–25 mg of chlorthalidone).
PMCID: PMC3373273  PMID: 22431578
hypertension; hypokalemia; hyperkalemia; diuretic; calcium-channel blocker; ACE-inhibitor
12.  Long-Term Follow-up of Participants with Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 
Circulation  2011;124(17):1811-1818.
In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/day) and lisinopril (10-40 mg/day) arms compared with the chlorthalidone (12.5-25 mg/day) arm . Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases.
Methods and Results
Using national databases, post-trial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%) with no significant differences by randomized treatment arm.
Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with development of HF is to be addressed.
PMCID: PMC3217334  PMID: 21969009
heart failure; hypertension; diuretics; mortality; ejection fraction
13.  Acceptance of a Polypill Approach to Prevent Cardiovascular Disease Among a Sample of U.S. Physicians 
Preventive medicine  2010;52(1):10-15.
Toex amine US physicians’ self-reported knowledge about the Polypill, factors considered in deciding whether to prescribe it, and acceptance of prescribing it for cardiovascular disease (CVD)prevention.
Numerical scales of 0 (lowest) to 5 (highest) were used to assess self -reported knowledge and importance of factors relevant to making a decision to prescribe a Polypill. Characteristics of physicians indicating they would prescribe a Polypill were compared.
Among 952 physicians surveyed February through March 2010, mean self-rated knowledge about the Polypill was 2.0±1.5. Importance of degree of CVD event reduction, cost, and side effects were rated with means of 4.4, 4.3, and 4.3, respectively. 83% of respondents indicated they would “definitely” or “probably” prescribe it for high-risk patients; 62% would do so for moderate risk patients. Physicians with self-rated knowledge at ≥75th percentile were more likely to indicate they would prescribe a Polypill for moderate risk ( adjusted OR 2.16; 95% CI 1.60–2.93) and high-risk (adjusted OR 1.57; 95% CI 1.07–2.32) patients.
Among this sample of physicians, there is relatively high acceptance of prescribing a Polypill for CVD prevention despite relatively modest knowledge about it.
PMCID: PMC3014398  PMID: 20933538
14.  The causal exposure model of vascular disease 
Primary prevention of cardiovascular disease is governed at present by the risk factor model for cardiovascular events, a model which is widely accepted by physicians and professional associations, but which has important limitations: most critically, that effective treatment to reduce arterial damage is often delayed until the age at which cardiovascular events become common. This delay means that many of the early victims of vascular disease will not be identified in time. This delay also allows atherosclerosis to develop and progress unchecked within the arterial tree with the result that the absolute effectiveness of preventive therapy is limited by the time it is eventually initiated. The causal exposure model of vascular disease is an alternative to the risk factor model for cardiovascular events. Whereas the risk factor model aims to identify and treat those at markedly increased risk of vascular events within the next decade, the causal exposure model of vascular disease aims to prevent events by treating the causes of the disease when they are identified. In the risk factor model, age is an independent non-modifiable risk factor and the predictive power of age far outweighs that of the other risk factors. In the causal exposure model, age is the duration of time the arterial wall is exposed to the causes of atherosclerosis: apoB (apolipoprotein B) lipoproteins, hypertension, diabetes and smoking. Preventing the development of advanced atherosclerotic lesions by treating the causes of vascular disease is the simplest, surest and most effective way to prevent clinical events.
PMCID: PMC3244267  PMID: 22187965
age; atherosclerosis; lipoprotein; prevention; risk factor; vascular disease; apo, apolipoprotein; BP, blood pressure; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin kexin 9
15.  Five years of Trials 
Trials  2011;12:248.
This editorial marks the launch of a special collection of articles highlighting 'Five years of Trials' ( The journal's achievements on its objectives since 2006 are described and some of the challenges still ahead are outlined - in particular further innovating in the reporting of trials and the publication of negative results. The other articles in this series are examples of where Trials has demonstrated progress on its objectives. These include the publication of raw data, extended versions of previously published trial-related articles, descriptions of 'lessons learned', negative results, and educational articles regarding ethics and reporting bias.
PMCID: PMC3254076  PMID: 22112799
16.  Suicidal Behavior and Depression in Smoking Cessation Treatments 
PLoS ONE  2011;6(11):e27016.
Two treatments for smoking cessation—varenicline and bupropion—carry Boxed Warnings from the U.S. Food and Drug Administration (FDA) about suicidal/self-injurious behavior and depression. However, some epidemiological studies report an increased risk in smoking or smoking cessation independent of treatment, and differences between drugs are unknown.
From the FDA's Adverse Event Reporting System (AERS) database from 1998 through September 2010 we selected domestic, serious case reports for varenicline (n = 9,575), bupropion for smoking cessation (n = 1,751), and nicotine replacement products (n = 1,917). A composite endpoint of suicidal/self-injurious behavior or depression was defined as a case with one or more Preferred Terms in Standardized MedDRA Query (SMQ) for those adverse effects. The main outcome measure was the ratio of reported suicide/self-injury or depression cases for each drug compared to all other serious events for that drug.
Overall we identified 3,249 reported cases of suicidal/self-injurious behavior or depression, 2,925 (90%) for varenicline, 229 (7%) for bupropion, and 95 (3%) for nicotine replacement. Compared to nicotine replacement, the disproportionality results (OR (95% CI)) were varenicline 8.4 (6.8–10.4), and bupropion 2.9 (2.3–3.7). The disproportionality persisted after excluding reports indicating concomitant therapy with any of 58 drugs with suicidal behavior warnings or precautions in the prescribing information. An additional antibiotic comparison group showed that adverse event reports of suicidal/self-injurious behavior or depression were otherwise rare in a healthy population receiving short-term drug treatment.
Varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. Bupropion for smoking cessation had smaller increased risks. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.
PMCID: PMC3206890  PMID: 22073240
17.  Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis 
There have been postmarketing reports of adverse cardiovascular events associated with the use of varenicline, a widely used smoking cessation drug. We conducted a systematic review and meta-analysis of randomized controlled trials to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.
We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, websites of regulatory authorities and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. We selected double-blind randomized controlled trials of at least one week’s duration involving smokers or people who used smokeless tobacco that reported on cardiovascular events (ischemia, arrhythmia, congestive heart failure, sudden death or cardiovascular-related death) as serious adverse events asociated with the use of varenicline.
We analyzed data from 14 double-blind randomized controlled trials involving 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo (1.06% [52/4908] in varenicline group v. 0.82% [27/3308] in placebo group; Peto odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09–2.71; I2 = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. There were too few deaths to allow meaningful comparisons of mortality.
Our meta-analysis raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.
PMCID: PMC3168618  PMID: 21727225
18.  Authors’ response 
PMCID: PMC3168638
19.  Authors’ response 
PMCID: PMC3168640
20.  Physical Activity and Incidence of Atrial Fibrillation in Older Adults: the Cardiovascular Health Study 
Circulation  2008;118(8):800-807.
Vigorous exertion and endurance training have been reported to increase atrial fibrillation (AF). Associations of habitual light or moderate activity with AF incidence have not been evaluated.
Methods and Results
We prospectively investigated associations of leisure-time activity, exercise intensity, and walking habits, assessed at baseline and updated during follow-up visits, with incident AF, diagnosed by annual 12-lead-electrocardiograms and hospital discharge records, from 1989–2001 among 5,446 adults ≥65 in the Cardiovascular Health Study. During 47,280 person-years follow-up, 1,061 new AF cases occurred (incidence=22.4/1,000 person-years). In multivariable-adjusted analyses, leisure-time activity was associated with lower AF incidence in a graded manner, with 25% (HR=0.75, 95%CI=0.61, 0.90), 22% (HR=0.78, 95%CI=0.65, 0.95), and 36% (HR=0.64, 95%CI=0.52, 0.79) lower risk in quintiles 3, 4, and 5, versus quintile 1 (p trend<0.001). Exercise intensity had a U-shaped relationship with AF (quadratic p=0.02): versus no exercise, AF incidence was lower with moderate (HR=0.72, 95%CI=0.58, 0.89), but not high (HR=0.87, 95%CI=0.64, 1.19), intensity exercise. Walking distance and pace were each associated with lower AF risk in a graded manner (p trend <0.001); assessing combined effects of distance/pace, individuals in quartile 2, 3, and 4 had 27% (HR=0.73, 95%CI=0.61, 0.86), 40% (HR=0.60, 95%CI=0.50, 0.73), and 48% (HR=0.52, 95%CI=0.42, 0.65) lower AF incidence, compared with quartile 1. Findings appeared unrelated to confounding by comorbidity or indication. Evaluating cutpoints of moderate leisure-time activity (~600 kcal/wk), walking distance (12 blocks/wk), and pace (2 mph), 26% of all new AF cases (95% CI=7, 43%) appeared attributable to absence of these activities.
Light to moderate physical activities, particularly leisure-time activity and walking, are associated with significantly lower AF incidence in older adults.
PMCID: PMC3133958  PMID: 18678768
arrhythmia; exercise; prevention; atrial fibrillation
21.  Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials 
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 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 I2 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; I2=0%). Both 10 µg (2.15, 1.03 to 4.51; P=0.04; I2=9%) and 5 µg (1.46, 1.01 to 2.10; P=0.04; I2=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.
PMCID: PMC3114950  PMID: 21672999
22.  Impact of the ALLHAT/JNC7 Dissemination Project on Thiazide-type Diuretic Use 
Archives of internal medicine  2010;170(10):851-858.
Strategies are needed to improve the translation of clinical trial results into practice. We assessed the impact of the ALLHAT/JNC7 Dissemination Project’s academic detailing component on thiazide-type diuretic prescribing (ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JNC7 indicates the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure).
We used two national databases available from IMS Health: a physician survey of medications reported for hypertension and a pharmacy dispensing database on antihypertensive medications. At a county level, we correlated medication data with Dissemination Project intensity. Practices before the Dissemination Project in 2004 were compared to those after its completion in 2007. We also examined 2000–2008 national trends.
Academic detailing reached 18,524 physicians in 1698 venues via 147 investigator-educators. We noted an association between ALLHAT/JNC7 academic detailing activities and increased prescribing of thiazide-type diuretics. Physician survey data showed that the percentage of hypertension visits where the physician recorded where a thiazide-type diuretic was noted increased the most in counties with the greatest activities (8.6%, from 37.9% to 46.5%) compared to counties with moderate-level (2% change), low-level (−2%) and no activities (2%, p for trend <0.05). Pharmacy dispensing data showed that thiazide-type diuretic prescribing increased by 8.7% in counties with Dissemination Project activities compared to 3.9% in those without activities (p<0.001). Nationally, thiazide-type diuretic use did not increase between 2004 and 2008.
The ALLHAT/JNC7 Dissemination Project was associated with a small effect on thiazide-type diuretic use consistent with its small dose and the potential of external factors to diminish its impact. Academic detailing may increase physicians’ implementation of clinical trial results thereby making prescribing more consistent with evidence.
PMCID: PMC2989728  PMID: 20498411
23.  A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization 
Trials  2011;12:3.
The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear. More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease (CVD), side effects, improvement in adherence and physician/patient "acceptability" of the Polypill.
We conducted an open-label, parallel-group, randomized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD. The trial compared a Polypill (75 mg aspirin, 20 mg simvastatin, 10 mg lisinopril and 12.5 mg hydrochlorothiazide) to Standard Practice. After randomization, patients were followed monthly for three months. Pre-specified primary outcomes included reduction in systolic blood pressure, total cholesterol and estimated 10-year CVD risk. We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients.
Patients were recruited in a six-month period as planned. Two hundred three patients (94.0%) completed the treatment program and returned for their three-month follow-up visits. No safety concerns were reported. These findings suggest a high rate of patient acceptability, a finding that is bolstered by the majority of patients completing the trial (90%) indicating that they would take the Polypill "for life" if proven to be effective in reducing CVD risk. Approximately 86% of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93% for secondary prevention of CVD. Both the Polypill and Standard Practice resulted in marked reductions in systolic blood pressure, total cholesterol and 10-year risk of CVD. However, the differences between the treatment groups were not statistically significant.
We successfully completed a Polypill feasibility trial in Sri Lanka. We were able to document high acceptability of the Polypill to patients and physicians. We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs. The Polypill was however simpler and achieved comparable risk factor reductions, highlighting its potential usefulness in the prevention of CVD.
Trial registration number
ISRCTN: NCT00567307
PMCID: PMC3023675  PMID: 21205325
24.  Prescription Drugs Associated with Reports of Violence Towards Others 
PLoS ONE  2010;5(12):e15337.
Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others.
To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association.
From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms.
Main Outcome Measures
Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a χ2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01).
We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs.
Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features.
PMCID: PMC3002271  PMID: 21179515
25.  Effect of ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women 
American journal of hypertension  2010;23(5):528-533.
Accumulating evidence suggests that ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure-lowering effects in humans is lacking.
We determined the effects of ginkgo biloba extract (240 mg/day) on blood pressure and incident hypertension in 3,069 participants (mean age, 79 yrs; 46% female; 96% White) from the Ginkgo Evaluation of Memory study. We also examined whether the treatment effects are modified by baseline hypertension status.
At baseline 54% of the study participants were hypertensive, 28% were pre-hypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in blood pressure and pulse pressure in the ginkgo biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of ginkgo biloba, it did influence the changes in blood pressure variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in pre-hypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the OR (95% CI) for being a never-user in the ginkgo biloba group was 0.75 (0.48–1.16). The rate of incident hypertension also did not differ between participants assigned to ginkgo biloba vs. placebo (HR, 0.99, 95% CI, 0.84–1.15).
Our data indicate that ginkgo biloba does not reduce blood pressure or the incidence of hypertension in elderly men and women.
PMCID: PMC2989407  PMID: 20168306
gingko biloba; blood pressure; hypertension; elderly

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