Maria Eberg

Use of Statins and the Risk of Death in Patients With Prostate Cancer

PURPOSE To determine whether the use of statins after prostate cancer diagnosis is associated with a decreased risk of cancer-related mortality and all-cause mortality and to assess whether this association is modified by prediagnostic use of statins. PATIENTS AND METHODS A cohort of 11,772 men newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, followed until October 1, 2012, was identified using a large population-based electronic database from the United Kingdom. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% CIs of mortality outcomes associated with postdiagnostic use of statins, lagged by 1 year to account for latency considerations and to minimize reverse causality, and considering effect modification by prediagnostic use of statins. RESULTS During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively). CONCLUSION Overall, the use of statins after diagnosis was associated with a decreased risk in prostate cancer mortality. However, this effect was stronger in patients who also used statins before diagnosis.

Meta-Analysis of Randomized Controlled Trials Comparing the Long-Term Outcomes of Carotid Artery Stenting Versus Endarterectomy

Background—Stenting is an endovascular alternative to endarterectomy for the management of carotid stenosis, but its long-term safety and efficacy relative to endarterectomy remain unclear. Our objective was to compare the safety and efficacy of stenting with those of endarterectomy, with a particular focus on long-term outcomes, via meta-analysis of randomized controlled trials (RCTs). Methods and Results—We systematically searched PubMed, EMBASE, MEDLINE, and the Cochrane Library for RCTs with ≥50 patients that compared stenting with endarterectomy in patients with carotid stenosis. Periprocedural and long-term outcomes were assessed, with data pooled across RCTs using random-effects models. Eight RCTs were included in our meta-analysis (n=7091), with follow-up ranging from 2.0 to 10.0 years. When compared with endarterectomy, stenting was associated with an increased risk of periprocedural stroke (relative risk, 1.49, 95% confidence interval [CI], 1.11 to 2.01; risk difference, 1.7%; 95% CI, 0.3 to 3.0) but a decreased risk of periprocedural myocardial infarction (relative risk, 0.47; 95% CI, 0.29 to 0.78; risk difference, −0.4%; 95% CI, −0.8% to 0.1%). During long-term follow-up, stenting was associated with an increased risk of stroke (relative risk, 1.36; 95% CI, 1.16 to 1.61) and a composite end point of ipsilateral stroke, periprocedural stroke, or periprocedural death (relative risk, 1.45; 95% CI, 1.20 to 1.75). Conclusions—Although stenting has more favorable periprocedural outcomes with respect to myocardial infarction, the observed increased risk of stroke and death throughout follow-up with stenting suggests that endarterectomy remains the treatment of choice for carotid stenosis.

5α-Reductase Inhibitors and the Risk of Cancer-Related Mortality in Men With Prostate Cancer

IMPORTANCE 5α-Reductase inhibitors (5-ARIs) are widely used in the treatment of benign prostatic hyperplasia. However, randomized clinical trials have raised concerns that their use may be associated with an increased risk of high-grade prostate cancer tumors that would ultimately lead to worse prostate cancer outcomes. To date, few observational studies have addressed this important safety concern. OBJECTIVE To determine whether the use of 5-ARIs before prostate cancer diagnosis is associated with an increased risk of cancer-specific and all-cause mortality in men with a new diagnosis of prostate cancer in the real-world setting. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted in a cohort of 13,892 men with a new diagnosis of prostate cancer between January 1, 1999, and December 31, 2009, who were followed up until October 1, 2012. Patients were individually linked across 4 databases from the United Kingdom: National Cancer Data Repository, Clinical Practice Research Datalink, Hospital Episodes Statistics database, and Office for National Statistics database. MAIN OUTCOMES AND MEASURES Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of prostate cancer-specific and all-cause mortality associated with prediagnostic use of 5-ARIs. For each outcome, 2 models were constructed, one adjusted for predefined covariates (conventional model) and another adjusted for high-dimensional propensity score (HD-PS) deciles. RESULTS During a mean (SD) of 4.5 (3.1) years, 5001 deaths occurred, including 2429 from prostate cancer (crude incidence rate of 3.86 per 100 person-years [95% CI, 3.71-4.02]). In the conventional model, use of 5-ARIs before prostate cancer diagnosis was not associated with an increased risk of prostate cancer-specific mortality (crude incidence rates, 3.76 [95% CI, 3.04-4.59] [use] vs 3.87 [95% CI, 3.71-4.03] [nonuse] per 100 person-years; adjusted hazard ratio [aHR], 0.86 [95% CI, 0.69-1.06]) and all-cause mortality (crude incidence rates, 8.42 [95% CI, 7.32-9.64] [use] vs 7.93 [95% CI, 7.71-8.16] [nonuse] per 100 person-years; aHR, 0.87; 95% CI, 0.75-1.00). Similar results were observed with the HD-PS adjusted model (prostate cancer-specific mortality: aHR, 0.90 [95% CI, 0.73-1.13]; and all-cause mortality: aHR, 0.92 [95% CI, 0.80-1.07]). CONCLUSIONS AND RELEVANCE The use of 5-ARIs was not associated with an increased risk of prostate cancer-specific and all-cause mortality in men with a new diagnosis of prostate cancer. While these results provide reassurance, additional studies are needed to replicate these findings.

Efficacy and Safety of Smoking Cessation Interventions in Patients With Cardiovascular Disease: A Network Meta-Analysis of Randomized Controlled Trials.

Background— Although the efficacy and safety of smoking cessation interventions are well established, their efficacy and safety in patients with cardiovascular disease (CVD) remain unclear. The objective of this study was to evaluate the efficacy and safety of pharmacological and behavioral smoking cessation interventions in CVD patients via a meta-analysis of randomized controlled trials. Methods and Results— EMBASE, PsycINFO, MEDLINE, PubMed, and the Cochrane Tobacco Addiction Specialized Register were searched for randomized controlled trials evaluating the efficacy of smoking cessation pharmacotherapies and behavioral therapies in CVD patients. Outcomes of interest were smoking abstinence at 6 and 12 months, defined using the most rigorous criteria reported. Data were pooled across studies for direct comparisons using random-effects models. Network meta-analysis using a graph-theoretical approach was used to generate the indirect comparisons. Seven pharmacotherapy randomized controlled trials (n=2809) and 17 behavioral intervention randomized controlled trials (n=4666) met our inclusion criteria. Our network meta-analysis revealed that varenicline (relative risk [RR]: 2.64; 95% confidence interval [CI], 1.34–5.21) and bupropion (RR: 1.42; 95% CI, 1.01–2.01) were associated with greater abstinence than placebo. The evidence about nicotine replacement therapies was inconclusive (RR: 1.22; 95% CI, 0.72–2.06). Telephone therapy (RR: 1.47; 95% CI: 1.15–1.88) and individual counseling (RR: 1.64, 95% CI: 1.17–2.28) were both more efficacious than usual care, whereas in-hospital behavioral interventions were not (RR: 1.05; 95% CI, 0.78–1.43). Conclusions— Our meta-analysis suggests varenicline and bupropion, as well as individual and telephone counseling, are efficacious for smoking cessation in CVD patients.

Prognostic value of atrial fibrillation inducibility after right atrial flutter ablation

BACKGROUND Patients with typical right atrial flutter (AFL) may also have underlying atrial fibrillation (AF) or be at high risk of developing AF. Inducibility of AF among patients undergoing AFL ablation may be an important predictor of future occurrence of AF and may be useful in guiding management of this patient population. OBJECTIVE This study aimed to determine whether inducibility of AF at the time of AFL ablation is independently associated with the risk of future AF. METHODS Attempt at induction of AF by burst pacing was performed in consecutive patients who underwent AFL ablation. Time to incidence of AF after AFL ablation was examined using multivariable Cox proportional hazards models. All analyses were stratified by a history of AF. RESULTS A total of 175 patients were retrospectively evaluated over a median follow-up period of 482 days. In patients without a documented history of AF (n = 93), the incidence of AF after AFL ablation was 18.7 per 100 person-years. In these patients, inducible AF was strongly associated with the future development of AF (adjusted hazard ratio 15.99; 95% confidence interval 5.10-50.12). In contrast, in patients with a documented history of AF (n = 82), the incidence of AF after AFL ablation was 59.3 per 100 person-years and inducible AF was not associated with the future development of AF (adjusted hazard ratio 1.26; 95% confidence interval 0.74-2.14). CONCLUSION Inducibility of AF after AFL ablation is strongly and independently associated with the risk of future AF among patients without a history of AF but not among patients with a history of AF.

Targeted Maximum Likelihood Estimation for Pharmacoepidemiologic Research

Background: Targeted maximum likelihood estimation has been proposed for estimating marginal causal effects, and is robust to misspecification of either the treatment or outcome model. However, due perhaps to its novelty, targeted maximum likelihood estimation has not been widely used in pharmacoepidemiology. The objective of this study was to demonstrate targeted maximum likelihood estimation in a pharmacoepidemiological study with a high-dimensional covariate space, to incorporate the use of high-dimensional propensity scores into this method, and to compare the results to those of inverse probability weighting. Methods: We implemented the targeted maximum likelihood estimation procedure in a single-point exposure study of the use of statins and the 1-year risk of all-cause mortality postmyocardial infarction using data from the UK Clinical Practice Research Datalink. A range of known potential confounders were considered, and empirical covariates were selected using the high-dimensional propensity scores algorithm. We estimated odds ratios using targeted maximum likelihood estimation and inverse probability weighting with a variety of covariate selection strategies. Results: Through a real example, we demonstrated the double robustness of targeted maximum likelihood estimation. We showed that results with this method and inverse probability weighting differed when a large number of covariates were included in the treatment model. Conclusions: Targeted maximum likelihood can be used in high-dimensional covariate settings. In high-dimensional covariate settings, differences in results between targeted maximum likelihood and inverse probability weighted estimation are likely due to sensitivity to (near) positivity violations. Further investigations are needed to gain better understanding of the advantages and limitations of this method in pharmacoepidemiological studies.

Use of statins and reduced risk of recurrence of VTE in an older population

We aimed to determine whether statin use is associated with a decreased risk of recurrent venous thromboembolism (VTE) in older patients. We used a pre-assembled cohort of patients at least 65 years of age diagnosed with incident VTE between January 1, 1994 and December 31, 2004 in the province of Québec, Canada and followed until December 31, 2005. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) of recurrent VTE associated with current and past use of statins, compared with non-use. The cohort included 25,681 patients with incident VTE. During a mean follow-up of 3.0 years, there were 2343 recurrent VTE events (rate: 3.1 per 100 person-years). Compared with non-use, current use of statins was associated with a decreased risk of VTE recurrence (rates: 1.55 vs 3.47 per 100 per year, respectively; HR: 0.74, 95 % CI: 0.61-0.89), while no association was observed with past use (HR: 0.98, 95 % CI: 0.76-1.25). In a secondary analysis, longer durations of statin use were associated with greater risk reductions (0-6 months, HR 0.82, 95 % CI: 0.67-1.01; 6-12 months, HR 0.62, 95 % CI: 0.43-0.90; ≥ 12 months, HR: 0.50, 95 % CI: 0.33-0.74; p-value for trend ≤ 0.001). The use of statin was associated with a decreased risk of recurrent VTE in older patients. This study supports the need for randomised controlled trials to assess the efficacy and safety of statins in the long-term treatment of VTE.

The Estimation of Gestational Age at Birth in Database Studies

Background: Studies on the safety of prenatal medication use require valid estimation of the pregnancy duration. However, gestational age is often incompletely recorded in administrative and clinical databases. Our objective was to compare different approaches to estimating the pregnancy duration. Methods: Using data from the Clinical Practice Research Datalink and Hospital Episode Statistics, we examined the following four approaches to estimating missing gestational age: (1) generalized estimating equations for longitudinal data; (2) multiple imputation; (3) estimation based on fetal birth weight and sex; and (4) conventional approaches that assigned a fixed value (39 weeks for all or 39 weeks for full term and 35 weeks for preterm). The gestational age recorded in Hospital Episode Statistics was considered the gold standard. We conducted a simulation study comparing the described approaches in terms of estimated bias and mean square error. Results: A total of 25,929 infants from 22,774 mothers were included in our “gold standard” cohort. The smallest average absolute bias was observed for the generalized estimating equation that included birth weight, while the largest absolute bias occurred when assigning 39-week gestation to all those with missing values. The smallest mean square errors were detected with generalized estimating equations while multiple imputation had the highest mean square errors. Conclusions: The use of generalized estimating equations resulted in the most accurate estimation of missing gestational age when birth weight information was available. In the absence of birth weight, assignment of fixed gestational age based on term/preterm status may be the optimal approach.

Population-Based Study on Patterns of Cardiac Stress Testing After Percutaneous Coronary Intervention

Background— The appropriate use criteria considers cardiac stress testing within 2 years after percutaneous coronary intervention (PCI) to be rarely appropriate, unless prompted by symptoms or change in clinical status. Little is known about the patterns of cardiac stress testing after PCI in the single-payer Canadian healthcare system, where mechanisms for reimbursement are different from the United States. Methods and Results— Frequency and timing of cardiac stress testing within 2 years of PCI performed between April 2004 and March 2013 in Ontario, Canada, was determined from linked provincial databases. Subsequent rates of coronary angiography and revascularization after stress testing were ascertained. Of the 112 691 patients with PCI, 67 442 (59.8%) underwent at least 1 stress test, with 38 267 (34.0%) undergoing repeat stress testing (ie, >1 stress test) within 2 years. Patients who underwent stress testing were younger, had less medical comorbidities, were more likely to reside in urban areas, and had higher incomes. Spikes in incidence of repeat stress testing were observed at 3 to 4 months, 6 to 7 months, and 12 to 13 months after the prior stress test. Of those tested, only 5.9% underwent subsequent coronary angiography, and only 3.1% underwent repeat revascularization within 60 days of stress testing. Conclusions— More than half of all patients undergo cardiac stress testing within 2 years of PCI, with one third undergoing repeat stress tests. Only 1 of 30 tested patients underwent repeat revascularization. These findings reinforce the appropriate use criteria recommendations against routine stress testing after PCI. Further work is needed to aid with the selection of patients most likely to benefit from stress testing after PCI.

Drospirenone-containing combined oral contraceptives and the risk of arterial thrombosis: a population-based nested case-control study.

To compare the rate of arterial thromboembolism (ATE) of drospirenone‐containing COCs to that of levonorgestrel‐containing COCs.