Objective

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.

Methods

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.

Results

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.

Conclusion

Among this sample of physicians, there is relatively high acceptance of prescribing a Polypill for CVD prevention despite relatively modest knowledge about it.

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.

This editorial marks the launch of a special collection of articles highlighting 'Five years of Trials' (http://www.trialsjournal.com/series/5years). 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.

Background

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.

Methodology

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.

Results

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.

Conclusions

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.

Background:

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.

Methods:

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.

Results:

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.

Interpretation:

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.

Background

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.

Conclusions

Light to moderate physical activities, particularly leisure-time activity and walking, are associated with significantly lower AF incidence in older adults.

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 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.

Background

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).

Methods

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.

Results

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.

Conclusions

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.

Objective

To examine associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults.

Methods

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).

Results

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%).

Conclusion

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.

Background

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.

Methods

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.

Results

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.

Conclusions

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

Background

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.

Methods

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.

Results

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).

Conclusions

Our data indicate that ginkgo biloba does not reduce blood pressure or the incidence of hypertension in elderly men and women.

Background

Previous research has suggested that emerging evidence from randomized controlled trials (RCTs) is often not reflected in physician selection of medication class for first-line anti-hypertensive therapy.

Objectives

To evaluate the association of RCT evidence in December 2002 from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) on use of anti-hypertensive medications over time in a multi-ethnic cohort.

Methods

The Multi-Ethnic Study of Atherosclerosis study, a prospective cohort study of 6,814 adults from 4 ethnic groups, had four separate assessments of drug use. Users of anti-hypertensive medications at baseline were excluded. We evaluated temporal changes in the medication class reported by new users of antihypertensive medications.

Results

After the exclusion of antihypertensive drug users at baseline, 32% of new users of anti-hypertensive drugs seen at exam 2 were prescribed a diuretic. The publication of ALLHAT was associated with a subsequent increase in the proportion of new users taking diuretics at exam 3 compared with exam 2 (Relative Risk (RR):1.31; 95% Confidence Interval (CI):1.09–1.59). After the report from ALLHAT, the proportion of users of diuretics seen at exam 3 rose to 44% (starting in 2004) and 39% in exam 4 (starting in 2005). This increase in the proportion of diuretic use among new users of anti-hypertensive medications declined slightly but could still be detected at exam 4 as compared to exam 2 (RR:1.28; 95% CI:1.04–1.57).

Conclusions

The randomized trial evidence from the ALLHAT study was temporally associated with a moderate increase in diuretic use.

Background

Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory (GEM) Study. The trial previously reported that Ginkgo biloba (G. biloba) had no effect on the primary outcome, incident dementia.

Methods and Results

The double-blind trial randomized 3069 participants over 75 years of age to 120 mg of G. biloba EGb 761 twice daily or placebo. Mean follow up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G. biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and gender. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G. biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207) or stroke (151) between G. biloba and placebo. There were 24 hemorrhagic strokes, 16 on G. biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease (PVD) events, 12 (0.8%) on G. biloba and 23 (1.5%) on placebo (p=0.04 exact test). Most of the PVD cases had either vascular surgery or amputation.

Conclusion

There was no evidence that G. biloba reduced total or CVD mortality or CVD events. There were more PVD events in the placebo arm. G. biloba cannot be recommended for preventing CVD. Further clinical trials of PVD outcomes might be indicated.

Objective To examine the association of myocardial infarction and stroke incidence with several commonly used two drug antihypertensive treatment regimens.

Design Population based case-control study.

Setting Group Health Cooperative, Seattle, WA, USA.

Participants Cases (n=353) were aged 30-79 years, had pharmacologically treated hypertension, and were diagnosed with a first fatal or non-fatal myocardial infarction or stroke between 1989 and 2005. Controls (n=952) were a random sample of Group Health members who had pharmacologically treated hypertension. We excluded individuals with heart failure, evidence of coronary heart disease, diabetes, or chronic kidney disease.

Exposures One of three common two drug combinations: diuretics plus β blockers; diuretics plus calcium channel blockers; and diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

Main outcome measures Myocardial infarction or stroke.

Results Compared with users of diuretics plus β blockers, users of diuretics plus calcium channel blockers had an increased risk of myocardial infarction (adjusted odds ratio (OR) 1.98, 95% confidence interval 1.37 to 2.87) but not of stroke (OR 1.02, 95% CI 0.63 to 1.64). The risks of myocardial infarction and stroke in users of diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers were slightly but not significantly lower than in users of diuretics plus β blockers (myocardial infarction: OR 0.76, 95% CI 0.52 to 1.11; stroke: OR 0.71, 95% CI 0.46 to 1.10).

Conclusions In patients with hypertension, diuretics plus calcium channel blockers were associated with a higher risk of myocardial infarction than other common two drug treatment regimens. A large trial of second line antihypertensive treatments in patients already on low dose diuretics is required to provide a solid basis for treatment recommendations.

Background

The prevalence and prognostic significance of isolated minor non-specific ST- segment and T-wave abnormalities (NSSTTA) in older adults are poorly understood.

Methods and Results

Cardiovascular Health Study participants free of both clinical cardiovascular disease (CVD) and major electrocardiographic abnormalities were included. We examined the prospective association of isolated minor NSSTTA (defined by Minnesota codes 4-3, 4-4, 5-3 and 5-4) with total, cardiovascular and coronary mortality, and incident non-fatal myocardial infarction (NFMI). Among 3224 participants (61.9% women, mean age 72 years), 233 (7.2%) had isolated NSSTTA at baseline. Covariates associated with isolated NSSTTA included older age, non-white race (20.5% of blacks vs. 4.8% of whites; P<0.001), diabetes, higher blood pressure and body mass index, but not presence of subclinical CVD. After 39,518 person-years of follow-up, presence of isolated NSSTTA was associated with significantly increased risk for coronary heart disease mortality (multivariable-adjusted hazards ratio 1.76; 95% confidence interval, 1.18-2.61) but not with incident NFMI (0.71; 0.43-1.17). The association of isolated NSSTTA with coronary death was independent of subclinical atherosclerosis and left ventricular mass measures. In secondary analyses among those with cardiac death, there was a significantly higher rate of primary arrhythmic death (32.3% vs. 15.4%; P=0.02) in participants with isolated NSSTTA versus those without NSSTTA.

Conclusions

Isolated NSSTTA are common in older Americans, and they are associated with significantly increased risk for coronary death. However, isolated NSSTTA are not associated with incident NFMI, suggesting the hypothesis that they are associated particularly with increased risk for primary arrhythmic death.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in inflammation and platelet function. Inherited deficiency and elevated levels are associated with atherosclerosis. Given potential common etiologies of atherosclerosis and venous thrombosis (VT), we hypothesized that low and high Lp-PLA2 would be associated with VT risk. Lp-PLA2 mass and activity were measured in baseline samples of Cardiovascular Health Study participants (5,888 men and women age ≥65), excluding 354 reporting pre-baseline VT. The study endpoint was VT unrelated to cancer after 11.6 years follow-up. Hazard ratios were estimated using Cox proportional hazard models, adjusting for age, race, sex and body-mass index. With 129 cases of VT, there was no association of Lp-PLA2 activity with risk. Adjusted hazard ratios were 1.19 (CI 0.62, 2.29) and 0.87 (CI 0.43, 1.76) for the lowest and highest decile, respectively, compared to the 10-25th percentile. Corresponding hazard ratios for Lp-PLA2 mass were 1.63 (CI 0.79, 3.34) and 1.33 (CI 0.61, 2.87). Results were robust to several definitions of low or high Lp-PLA2. While the association of Lp-PLA2 levels with arterial disease events implies a role for this enzyme in atherogenesis, our findings suggest that it is not prothrombotic.

Objective

To evaluate the cost-effectiveness of first-line treatments for hypertension.

Background

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint, so differences in costs may be critical for optimizing decision-making.

Methods

Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty.

Results

Over a patient’s lifetime, chlorthalidone was always least expensive (mean $4,802 less than amlodipine, $3,700 less than lisinopril). Amlodipine provided more life-years (LYs) than chlorthalidone in 84% of bootstrap samples (mean 37 days) at an incremental cost-effectiveness ratio of $48,400 per LY gained. Lisinopril provided fewer LYs than chlorthalidone in 55% of bootstrap samples (mean 7-day loss) despite a higher cost. At a threshold of $50,000 per LY gained, amlodipine was preferred in 50%, chlorthalidone in 40%, and lisinopril in 10% of bootstrap samples, but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen. Incorporating quality of life did not appreciably alter the results. Overall, no reasonable combination of assumptions led to 1 treatment being preferred in over 90% of bootstrap samples.

Conclusions

Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine, but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative. A randomized trial with power to exclude “clinically important” differences in survival will often have inadequate power to determine the most cost-effective treatment.

Background

Rosiglitazone and pioglitazone may increase the incidence of fractures. We aimed to determine systematically the risk of fractures associated with thiazolidinedione therapy and to evaluate the effect of the therapy on bone density.

Methods

We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), other trial registries and product information sheets through June 2008. We selected long-term (≥ 1 year) randomized controlled trials involving patients with type 2 diabetes and controlled observational studies that described the risk of fractures or changes in bone density with thiazolidinediones. We calculated pooled odds ratios (ORs) for fractures and the weighted mean difference in bone density.

Results

We analyzed data from 10 randomized controlled trials involving 13 715 participants and from 2 observational studies involving 31 679 participants. Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% confidence interval [CI] 1.18–1.79; p < 0.001). Five randomized controlled trials showed a significantly increased risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; p < 0.001) but not among men (OR 1.00, 95% CI 0.73–1.39; p = 0.98). The 2 observational studies demonstrated an increased risk of fractures associated with rosiglitazone and pioglitazone. Bone mineral density in women exposed to thiazolidinediones was significantly reduced at the lumbar spine (weighted mean difference –1.11%, 95% CI –2.08% to –0.14%; p = 0.02) and hip (weighted mean difference –1.24%, 95%CI –2.34% to –0.67%; p < 0.001) in 2 randomized controlled trials.

Interpretation

Long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.

Contradictory statements about the non-steroidal anti-inflammatory drugs from the European Medicines Agency and the United States Food and Drug Administration have raised questions about whether regulatory decisions are evidence-based. For the selective COX-2 inhibitors, there are clear contraindications and warnings in Europe, but only a vaguely worded Black Box warning in the United States. All the non-selective agents are given an almost "clean bill of health" in Europe, while all of them are judged to have a similar risk-benefit ratio as celecoxib in the United States. The regulatory agencies have failed to recognize the clinical trial evidence that the risk of cardiovascular events varies substantially among the non-selective agents, with diclofenac carrying the highest risk of harm.

This editorial introduces the new online, open access, peer-reviewed journal Trials. The journal considers manuscripts on any aspect of the design, performance, and findings of randomised controlled trials in any discipline related to health care, and also encourages the publication of protocols. Trialists will be able to provide the necessary detail for a true and complete scientific record. They will be able to communicate not only all outcome measures, as well as varying analyses and interpretations, but also in-depth descriptions of what they did and honest reflections about what they learnt.

Trials also encourages articles covering generic issues related to trials, for example focussing on the design, conduct, analysis, interpretation, or reporting.

A large number of randomized clinical trials with important health outcomes are completed each year. Those with favorable findings are typically reported and published rapidly, while the publication of those with unfavorable results is often delayed or given a positive "spin." This observation applies primarily to industry-sponsored trials. Our objectives are to discuss the responsibility of pharmaceutical firms to the public with respect to timely, complete, and unbiased information from all randomized clinical trials and to propose solutions for improvements. We believe that in addition to financial obligations to their shareholders, pharmaceutical companies have social responsibilities to the public and to health care providers. However, private markets do not reward or compel optimal disclosure of drug safety or inferiority information on a voluntary basis.

A problem which has not previously been identified relates to non-comparability of drugs. A case report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) illustrates how public interests may be violated due to failure to inform about drug inferiority. The current system for dissemination of relevant medical information could be improved if all involved parties collaborated fully. However, full disclosure of trial results is unlikely when research results are unfavorable to the firm. We conclude that expanded government regulations will be required for a satisfactory solution to the problem.