History of cardiovascular events and cardiovascular risk factors among patients initiating strontium ranelate for treatment of osteoporosis.

PURPOSE: To estimate the proportion of osteoporosis patients in whom initiating strontium ranelate treatment, under new EMA guidelines, should be contraindicated because of a history of cardiovascular events or risk for cardiovascular events. MATERIALS AND METHODS: This was a retrospective analysis of medical and pharmacy claims using the Clinical Practice Research Datalink database. Patients were included if they had ≥1 prescription of strontium from September 1, 2008 to August 31, 2013, were aged ≥50 as of the index date (the date of the first ever strontium ranelate prescription), and had ≥1 year of medical records pre-index. Cardiovascular events occurring any time pre-index were identified, which included ischemic heart disease, cerebrovascular disease, uncontrolled hypertension, and peripheral arterial disease. Cardiovascular risk factors assessed included 1) diabetes or hypertension any time pre-index; 2) hyperlipidemia in the 12 months pre-index; or 3) obesity in the 12 months pre-index. RESULTS: A total of 7,474 patients were included: 90.4% were women, with an average age of 76.5 years, and 84.5% used osteoporosis therapy, either bisphosphonates or non-bisphosphonates, prior to strontium initiation. A total of 23.6% of patients experienced ≥1 cardiovascular event prior to strontium initiation; the rate was lower among female patients than in male patients (22.4% vs 35.3%, P<0.01). A total of 45.9% had risk factors for cardiovascular events (without cardiovascular event history). CONCLUSION: More than one-fifth of osteoporosis patients in the UK who used strontium had a cardiovascular event history, and one-half had cardiovascular risk factors prior to strontium initiation.

Boceprevir and telaprevir for the treatment of chronic hepatitis C genotype 1 infection: an indirect comparison meta-analysis.

BACKGROUND: The aim of this study was to examine the relative efficacy and safety of boceprevir and telaprevir, when used in combination with pegylated interferon alpha and ribavirin, using an indirect comparison meta-analysis. METHODS: Published phase II and phase III randomized placebo-controlled trials examining the efficacy of boceprevir and telaprevir in chronic hepatitis C virus genotype 1 infected adult populations were included. The primary outcomes were sustained virologic response, relapse, and discontinuation of all study drugs. Secondary outcomes included the adverse events of anemia, neutropenia, rash, and pruritus. RESULTS: Four boceprevir trials and six telaprevir trials were included. No significant differences were observed for sustained virologic response among either naïve (relative risk [RR] 1.14, 95% confidence interval [CI] 0.93-1.37, P = 0.20) or experienced patients (RR 0.81, 95% CI 0.52-1.23, P = 0.30). Similarly, for relapse among naïve (RR 0.80, 95% CI 0.18-3.45, P = 0.77) and experienced patients (RR 1.71, 95% CI 0.90-3.24, P = 0.10), or discontinuation of therapy for naïve (RR 0.80, 95% CI 0.28-2.29, P = 0.72) and experienced patients (RR 0.88, 95% CI 0.69-1.12, P = 0.30). Telaprevir was more likely to be associated with rash and pruritus, and boceprevir was more likely to be associated with neutropenia in certain patient populations. CONCLUSION: Boceprevir and telaprevir appear comparable in terms of sustained virologic response, relapse, or discontinuation of therapy for patients treated with standard-dose therapy durations and response-guided therapy durations.

Differences in clinical outcomes among hepatitis C genotype 1-infected patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin: a meta-analysis.

BACKGROUND: With the development of new direct acting antiviral (DAA) therapy for hepatitis C, the backbone peginterferon alpha used may be of importance in maximizing treatment outcomes. To this end, the rates of sustained virologic response (SVR), relapse, and treatment discontinuation among hepatitis C genotype 1-infected patients given peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin were determined using a meta-analysis. METHODS: Randomized trials examining peginterferon alpha-2a or peginterferon alpha-2b co-administered with ribavirin for 48 weeks were included. Data were extracted on SVR, relapse, and treatment discontinuations for treatment-naïve and treatment-experienced patients. Pooled proportions using fixed and random effects meta-analysis were calculated. RESULTS: Twenty-six trials provided data on patients treated with peginterferon alpha-2a plus ribavirin, and 19 trials provided data on patients treated with peginterferon alpha-2b plus ribavirin. Five trials were direct head-to-head evaluations. In the subset of trials that included head-to-head evaluations, no significant differences were observed between the two treatments for treatment-naïve (relative risk [RR]: 1.07, 95% confidence intervals [CI]: 0.97-1.18) and treatment-experienced patients (RR: 1.27, 95% CI: 0.58-2.77). Using only active trial arms, a larger proportion of the treatment- naïve patients who were provided peginterferon alpha-2a plus ribavirin achieved a SVR (47%), which is greater than that of treatment-naïve patients who were provided peginterferon alpha- 2b plus ribavirin (40% SVR achievement); however, a larger proportion of treatment- experienced patients who were provided peginterferon alpha-2b plus ribavirin achieved a SVR (16%) when compared with treatment-experienced patients given peginterferon alpha-2a plus ribavirin (12% SVR achievement). A larger proportion of relapses occurred among both treatment-naïve and treatment-experienced patients given peginterferon alpha-2a plus ribavirin, when compared with treatment-naïve and treatment-experienced patients taking peginterferon alpha-2b plus ribavirin. The proportion of patients discontinuing treatment was greater among treatment-naïve patients taking peginterferon alpha-2a plus ribavirin, but smaller among treatment-experienced patients. CONCLUSION: There are small differences in treatment outcomes for different types of peginterferon- alpha. Patient status and complexity of administration may differentiate clinical outcomes.

Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients.

AIMS: Statin therapy is associated with important benefits for patients at risk of, and with, established cardiovascular disease. There is widespread interest in whether intensive dosing of statins yields larger treatment effects. We aimed to determine if intensive dosing is clinically important using a meta-analysis of randomized clinical trials (RCTs). METHODS: We conducted comprehensive searches of electronic databases from inception to December 2010. We included any RCT evaluating a larger dose with a clinically common dose. Two reviewers independently extracted data, in duplicate. We performed random-effects meta-analysis and a trial sequential analysis. RESULTS: We identified 10 RCTs enrolling a total of 41 778 participants. Trials followed patients for a mean of 2.5 years. We did not find statistically significant effects on all-cause mortality [relative risk (RR) 0.92, 95% confidence interval (CI), 0.83-1.03, P = 0.14, I(2) = 38%] or cardiovascular disease (CVD) deaths (RR 0.89, 95% CI, 0.78-1.01, P = 0.07, I(2) = 34%). When we pooled the composite endpoint of coronary heart disease (CHD) death plus non-fatal myocardial infarction (MI), we found a significant protective effect of intensive statin dosing (RR 0.90, 95% CI, 0.84-0.96, P ≤ 0.0001, I(2) = 0%). We also found a significant effect on non-fatal MIs (RR 0.82, 95% CI, 0.76-0.89, P ≤ 0.0001, I(2) = 0%) and a significant reduction in the composite of fatal and non-fatal strokes (excluding transient ischaemic attacks) reported in 10 RCTs (RR 0.86, 95% CI, 0.77-0.96, P = 0.006, I(2) = 0%). A subgroup analysis of three trials examining acute coronary syndrome patients found significant effects on all-cause (RR 0.75, 95% CI, 0.61-0.91, P = 0.005, I(2) = 0%) and CVD mortality (RR 0.74, 95% CI, 0.59-0.94, P = 0.013, I(2) = 0%) with intensive dosing. Applying an analysis of optimal information size on the primary analysis, we found that the evidence for CHD death plus non-fatal MIs is conclusive. The evidence for CVD deaths alone is not yet conclusive. CONCLUSIONS: Available evidence suggests that intensive statin therapy reduces the risk of non-fatal events and may have a role in reducing mortality.

Estimating the power of indirect comparisons: a simulation study.

BACKGROUND: Indirect comparisons are becoming increasingly popular for evaluating medical treatments that have not been compared head-to-head in randomized clinical trials (RCTs). While indirect methods have grown in popularity and acceptance, little is known about the fragility of confidence interval estimations and hypothesis testing relying on this method. METHODS: We present the findings of a simulation study that examined the fragility of indirect confidence interval estimation and hypothesis testing relying on the adjusted indirect method. FINDINGS: Our results suggest that, for the settings considered in this study, indirect confidence interval estimation suffers from under-coverage while indirect hypothesis testing suffers from low power in the presence of moderate to large between-study heterogeneity. In addition, the risk of overestimation is large when the indirect comparison of interest relies on just one trial for one of the two direct comparisons. INTERPRETATION: Indirect comparisons typically suffer from low power. The risk of imprecision is increased when comparisons are unbalanced.

Incorporating multiple interventions in meta-analysis: an evaluation of the mixed treatment comparison with the adjusted indirect comparison.

BACKGROUND: Comparing the effectiveness of interventions is now a requirement for regulatory approval in several countries. It also aids in clinical and public health decision-making. However, in the absence of head-to-head randomized trials (RCTs), determining the relative effectiveness of interventions is challenging. Several methodological options are now available. We aimed to determine the comparative validity of the adjusted indirect comparisons of RCTs with the mixed treatment comparison approach. METHODS: Using systematic searching, we identified all meta-analyses evaluating more than 3 interventions for a similar disease state with binary outcomes. We abstracted data on each clinical trial including population n and outcomes. We conducted fixed effects meta-analysis of each intervention versus mutual comparator and then applied the adjusted indirect comparison. We conducted a mixed treatment meta-analysis on all trials and compared the point estimates and 95% confidence/credible intervals (CIs/CrIs) to determine important differences. RESULTS: We included data from 7 reviews that met our inclusion criteria, allowing a total of 51 comparisons. According to the a priori consistency rule, we found 2 examples where the analytic comparisons were statistically significant using the mixed treatment comparison over the adjusted indirect comparisons and 1 example where this was vice versa. We found 6 examples where the direction of effect differed according to the indirect comparison method chosen and we found 9 examples where the confidence intervals were importantly different between approaches. CONCLUSION: In most analyses, the adjusted indirect comparison yields estimates of relative effectiveness equal to the mixed treatment comparison. In less complex indirect comparisons, where all studies share a mutual comparator, both approaches yield similar benefits. As comparisons become more complex, the mixed treatment comparison may be favoured.

Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis.

OBJECTIVE: To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions. DESIGN: Systematic review and meta-regression analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field. STUDY SELECTION: In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months. DATA EXTRACTION AND SYNTHESIS: Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated. RESULTS: The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterol alone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2% (95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class. CONCLUSIONS: Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.

HIV/AIDS in African militaries: an ecological analysis.

The HIV/AIDS pandemic is considered a security threat. Policy-makers have warned of destabilization of militaries due to massive troop deaths. Estimates of the rate of HIV within African militaries have been as high as 90 per cent. We aimed to determine if HIV prevalence within African militaries is higher than their host nation prevalence rates. Using systematic searching and access to United States Department of Defense data, we abstracted data on prevalence within militaries and their host communities. We conducted a random effects pooled analysis to determine differences in HIV prevalence rates in the military versus the host population. We obtained data on 21 African militaries. In general, HIV prevalence within the military is elevated compared to the general population. The differences were significant (odds ratio 1.97, 95% confidence interval: 1.58-2.45, P < 0.001). Further, inflated rates of HIV in militaries compared to non-military males of similar age were also significant (6.09, 4.47-8.30, P < or = 0.0001). States with recent conflicts and wars had elevated military rates, but these were also not significant (P = 0.4). Population levels predicted military prevalence rates (P < or = 0.001). HIV/AIDS prevalence rates in most African militaries are significantly elevated compared to their host communities.

Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients.

PURPOSE: More than 120,000 patients now have taken part in randomized trials evaluating statin therapy for stroke prevention. We aimed to conduct a comprehensive review of all randomized trials and determine the therapeutic potential of statins for all strokes. METHODS: We searched 10 electronic databases (from inception to December 2006). We additionally contacted study authors and authors of previous reviews. We extracted data on study characteristics and outcomes related to all-cause mortality, all-stroke incidence, specific type of strokes, and cholesterol changes. We pooled data using a random-effects model and conducted meta-regression. RESULTS: We included 42 trials assessing statin therapy for all-stroke prevention (n=121,285), resulting in a pooled relative risk (RR) of 0.84 (95% confidence interval [CI], 0.79-0.91). The pooled RR of statin therapy for all-cause mortality (n=116,080) was 0.88 (95% CI, 0.83-0.93). Each unit increase in low-density lipoprotein (LDL) resulted in a 0.3% increased RR of death (P=.02). Seventeen trials evaluated statins on cardiovascular death (n=57,599, RR 0.81, 95% CI, 0.74-0.90), and 11 evaluated nonhemorrhagic cerebrovascular events (n=58,604, RR 0.81, 95% CI, 0.69-0.94). Eleven trials reported hemorrhagic stroke incidence (total n=54,334, RR 0.94, 95% CI, 0.68-1.30) and 21 trials reported on fatal strokes (total n=82,278, RR 0.99, 95% CI, 0.80-1.21). Only one trial reported on statin therapy for secondary prevention. CONCLUSIONS: Statin therapy provides high levels of protection for all-cause mortality and nonhemorrhagic strokes. This overview reinforces the need to consider prolonged statin treatment in patients at high risk of major vascular events, but caution remains for patients at risk of bleeds.