Future research prioritization in cardiac resynchronization therapy.

BACKGROUND: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan. METHODS: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers. RESULTS: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD. CONCLUSIONS: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review.

Background: The comparative safety and effectiveness of treatments to prevent thromboembolic complications in atrial fibrillation (AF) remain uncertain. Purpose: To compare the effectiveness of medical and procedural therapies in preventing thromboembolic events and bleeding complications in adults with nonvalvular AF. Data Sources: English-language studies in several databases from 1 January 2000 to 14 February 2018. Study Selection: Two reviewers independently screened citations to identify comparative studies of treatments to prevent stroke in adults with nonvalvular AF who reported thromboembolic or bleeding complications. Data Extraction: Two reviewers independently abstracted data, assessed study quality and applicability, and rated strength of evidence. Data Synthesis: Data from 220 articles were included. Dabigatran and apixaban were superior and rivaroxaban and edoxaban were similar to warfarin in preventing stroke or systemic embolism. Apixaban and edoxaban were superior and rivaroxaban and dabigatran were similar to warfarin in reducing the risk for major bleeding. Treatment effects with dabigatran were similar in patients with renal dysfunction (interaction P > 0.05), and patients younger than 75 years had lower bleeding rates with dabigatran (interaction P < 0.001). The benefit of treatment with apixaban was consistent in many subgroups, including those with renal impairment, diabetes, and prior stroke (interaction P > 0.05 for all). The greatest bleeding risk reduction was observed in patients with a glomerular filtration rate less than 50 mL/min/1.73 m2 (P = 0.003). Similar treatment effects were observed for rivaroxaban and edoxaban in patients with prior stroke, diabetes, or heart failure (interaction P > 0.05 for all). Limitation: Heterogeneous study populations, interventions, and outcomes. Conclusion: The available direct-acting oral anticoagulants (DOACs) are at least as effective and safe as warfarin for patients with nonvalvular AF. The DOACs had similar benefits across several patient subgroups and seemed safe and efficacious for a wide range of patients with nonvalvular AF. Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069999).

Systematic review and meta-analysis of endovascular and surgical revascularization for patients with chronic lower extremity venous insufficiency and varicose veins.

BACKGROUND: Chronic lower extremity venous disease (LECVD) is twice as prevalent as coronary heart disease, and invasive therapies to treat LECVD accounted for an estimated $290 million in Medicare expenditures in 2015. Despite increasing use of these invasive therapies, their comparative effectiveness is unknown. METHODS: We conducted a systematic review and meta-analysis of treatments for patients (symptomatic and asymptomatic) with lower extremity varicosities and/or lower extremity chronic venous insufficiency/incompetence/reflux. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English-language studies published from January 2000 to July 2016. We included comparative randomized controlled trials (RCTs) with >20 patients and observational studies with >500 patients. Short-, intermediate-, and long-term outcomes of placebo, mechanical compression therapy, and invasive therapies (surgical and endovascular) were included. Quality ratings and evidence grading was performed. Random-effects models were used to compute summary estimates of effects. RESULTS: We identified a total of 57 studies representing 105,878 enrolled patients, including 53 RCTs comprised of 10,034 patients. Among the RCTs, 16 were good quality, 28 were fair quality, and 9 were poor quality. Allocation concealment, double blinding, and reporting bias were inadequately addressed in 25 of 53 (47%), 46 of 53 (87%), and 15 of 53 (28.3%), respectively. Heterogeneity in therapies, populations, and/or outcomes prohibited meta-analysis of comparisons between different endovascular therapies and between endovascular intervention and placebo/compression. Meta-analysis evaluating venous stripping plus ligation (high ligation/stripping) compared with radiofrequency ablation revealed no difference in short-term bleeding (odds ratio [OR]=0.30, 95% CI -0.16 to 5.38, P=.43) or reflux recurrence at 1-2 years (OR=0.76, 95% CI 0.37-1.55, P=.44). Meta-analysis evaluating high ligation/stripping versus endovascular laser ablation revealed no difference in long-term symptom score (OR 0.02, 95% CI -0.19 to 0.23, P=.84) or quality of life at 2 years (OR 0.06, 95% CI -0.12 to 0.25, P=.50). CONCLUSIONS: The paucity of high-quality comparative effectiveness and safety data in LECVD is concerning given the overall rise in endovascular procedures. More high-quality studies are needed to determine comparative effectiveness and guide policy and practice.

Diagnostic Accuracy of Screening Tests and Treatment for Post-Acute Coronary Syndrome Depression: A Systematic Review.

BACKGROUND: Patients who have had an acute coronary syndrome (ACS) event have an increased risk for depression. PURPOSE: To evaluate the diagnostic accuracy of depression screening instruments and to compare safety and effectiveness of depression treatments in adults within 3 months of an ACS event. DATA SOURCES: MEDLINE, EMBASE, PsycINFO, CINAHL, and Cochrane Database of Systematic Reviews from January 2003 to August 2017, and a manual search of citations from key primary and review articles. STUDY SELECTION: English-language studies of post-ACS patients that evaluated the diagnostic accuracy of depression screening tools or compared the safety and effectiveness of a broad range of pharmacologic and nonpharmacologic depression treatments. DATA EXTRACTION: 2 investigators independently screened each article for inclusion; abstracted the data; and rated the quality, applicability, and strength of evidence. DATA SYNTHESIS: Evidence from 6 of the 10 included studies showed that a range of depression screening instruments produces acceptable levels of diagnostic sensitivity, specificity, and negative predictive values (70% to 100%) but low positive predictive values (below 50%). The Beck Depression Inventory-II was the most studied tool. A large study found that a combination of cognitive behavioral therapy (CBT) and antidepressant medication improved depression symptoms, mental health-related function, and overall life satisfaction more than usual care. LIMITATION: Few studies, no evaluation of the influence of screening on clinical outcomes, and no studies addressing several clinical interventions of interest. CONCLUSION: Depression screening instruments produce diagnostic accuracy metrics that are similar in post-ACS patients and other clinical populations. Depression interventions have an uncertain effect on cardiovascular outcomes, but CBT combined with antidepressant medication produces modest improvement in psychosocial outcomes. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality (PROSPERO: CRD42016047032).

AHRQ EPC Series on Improving Translation of Evidence: Web-Based Interactive Presentation of Systematic Review Reports.

Systematic reviews are used by a diverse range of users to address an ever-expanding set of questions and needs. It is unlikely that a single static report will efficiently satisfy the different needs of diverse users. METHODS: An open-source Web-based interactive report presentation of a systematic review was developed to allow users to generate their own "reports" from the information produced by the review. Data from a broad-scope systematic review were used with network meta-analysis conducted on nonsurgical treatments of urinary incontinence (UI) in women. Stakeholders informed and piloted the tool and assessed its usefulness. RESULTS: The final tool allows users to obtain descriptive and analytic results for a network of treatment categories and various outcomes (cure, improvement, satisfaction, quality of life, adverse events) across several subgroups (all women, older women, or those with stress or urgency UI), along with study-level information, and overall conclusions. The stakeholders were satisfied with the functionality of the tool and proposed a number of improvements regarding presentation (for example, present information on numbers of trials in figures), analyses (for example, allow on-the-fly subgroup analyses, explore trade-offs between several outcomes), and information sharing (for example, provide ability to import/export data from/to other software). CONCLUSION: A prototype tool to present customized analyses from broad-scope systematic reviews is presented. Further improvements are suggested to develop a scalable tool to make systematic reviews useful to increasingly diverse user groups.

Predicting Thromboembolic and Bleeding Event Risk in Patients with Non-Valvular Atrial Fibrillation: A Systematic Review.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of stroke. Medical therapy for decreasing stroke risk involves anticoagulation, which may increase bleeding risk for certain patients. In determining the optimal therapy for stroke prevention for patients with AF, clinicians use tools with various clinical, imaging and patient characteristics to weigh stroke risk against therapy-associated bleeding risk. AIM: This article reviews published literature and summarizes available risk stratification tools for stroke and bleeding prediction in patients with AF. METHODS: We searched for English-language studies in PubMed, Embase and the Cochrane Database of Systematic Reviews published between 1 January 2000 and 14 February 2018. Two reviewers screened citations for studies that examined tools for predicting thromboembolic and bleeding risks in patients with AF. Data regarding study design, patient characteristics, interventions, outcomes, quality, and applicability were extracted. RESULTS: Sixty-one studies were relevant to predicting thromboembolic risk and 38 to predicting bleeding risk. Data suggest that CHADS2, CHA2DS2-VASc and the age, biomarkers, and clinical history (ABC) risk scores have the best evidence for predicting thromboembolic risk (moderate strength of evidence for limited prediction ability of each score) and that HAS-BLED has the best evidence for predicting bleeding risk (moderate strength of evidence). LIMITATIONS: Studies were heterogeneous in methodology and populations of interest, setting, interventions and outcomes analysed. CONCLUSION: CHADS2, CHA2DS2-VASc and ABC scores have the best prediction for stroke events, and HAS-BLED provides the best prediction for bleeding risk. Future studies should define the role of imaging tools and biomarkers in enhancing the accuracy of risk prediction tools. PRIMARY FUNDING SOURCE: Patient-Centered Outcomes Research Institute (PROSPERO #CRD42017069999).

Nonpharmacologic Treatments for Attention-Deficit/Hyperactivity Disorder: A Systematic Review.

CONTEXT: Nonpharmacologic treatments for attention-deficit/hyperactivity disorder (ADHD) encompass a range of care approaches from structured behavioral interventions to complementary medicines. OBJECTIVES: To assess the comparative effectiveness of nonpharmacologic treatments for ADHD among individuals 17 years of age and younger. DATA SOURCES: PubMed, Embase, PsycINFO, and Cochrane Database of Systematic Reviews for relevant English-language studies published from January 1, 2009 through November 7, 2016. STUDY SELECTION: We included studies that compared any ADHD nonpharmacologic treatment strategy with placebo, pharmacologic, or another nonpharmacologic treatment. DATA EXTRACTION: Study design, patient characteristics, intervention approaches, follow-up times, and outcomes were abstracted. For comparisons with at least 3 similar studies, random-effects meta-analysis was used to generate pooled estimates. RESULTS: We identified 54 studies of nonpharmacologic treatments, including neurofeedback, cognitive training, cognitive behavioral therapy, child or parent training, dietary omega fatty acid supplementation, and herbal and/or dietary approaches. No new guidance was identified regarding the comparative effectiveness of nonpharmacologic treatments. Pooled results for omega fatty acids found no significant effects for parent rating of ADHD total symptoms (n = 411; standardized mean difference -0.32; 95% confidence interval -0.80 to 0.15; I2 = 52.4%; P = .10) or teacher-rated total ADHD symptoms (n = 287; standardized mean difference -0.08; 95% confidence interval -0.47 to 0.32; I2 = 0.0%; P = .56). LIMITATIONS: Studies often did not reflect the primary care setting and had short follow-up periods, small sample sizes, variations in outcomes, and inconsistent reporting of comparative statistical analyses. CONCLUSIONS: Despite wide use, there are significant gaps in knowledge regarding the effectiveness of ADHD nonpharmacologic treatments.

Oral contraceptive use for the primary prevention of ovarian cancer.

OBJECTIVE: To estimate the overall balance of harms and benefits from the potential use of oral contraceptives (OCs) for the primary prevention of ovarian cancer DATA SOURCES: We searched PubMed®, Embase®, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for English-language studies published from January 1990 to June 2012 that evaluated the potential benefits (reduction in ovarian, colorectal, and endometrial cancers) and harms (increase in breast and cervical cancer, and vascular complications) of OC use. REVIEW METHODS: Two investigators screened each abstract and full-text article for inclusion; the investigators abstracted data, and they performed quality ratings, applicability ratings, and evidence grading. Random-effects models were used to compute summary estimates of effects. A simulation model was used to estimate the effects of OC use on the overall balance of benefits and harms. RESULTS: We reviewed 55 studies relevant to ovarian cancer outcomes, 66 relevant to other cancers, and 50 relevant to vascular events. Ovarian cancer incidence was significantly reduced in OC users (OR [odds ratio], 0.73; 95% CI [confidence interval], 0.66 to 0.81), with greater reductions seen with longer duration of use. Breast cancer incidence was slightly but significantly increased in OC users (OR, 1.08; 95% CI, 1.00 to 1.17), with a significant reduction in risk as time since last use increased. The risk of cervical cancer was significantly increased in women with persistent human papillomavirus infection who used OCs, but heterogeneity prevented a formal meta-analysis. Incidences of both colorectal cancer (OR, 0.86; 95% CI, 0.79 to 0.95) and endometrial cancer (OR, 0.57; 95% CI, 0.43 to 0.76) were significantly reduced by OC use. The risk of vascular events was increased in current OC users compared with nonusers, although the increase in myocardial infarction was not statistically significant. The overall strength of evidence for ovarian cancer prevention was moderate to low, primarily because of the lack of randomized trials and inconsistent reporting of important characteristics of use, such as duration. The simulation model predicted that the combined increase in risk of breast and cervical cancers and vascular events was likely to be equivalent to or greater than the decreased risk in ovarian cancer, although the harm/benefit ratio was much more favorable when protection against endometrial and colorectal cancers was added, resulting in net gains in life expectancy of approximately 1 month. CONCLUSIONS: There is insufficient evidence to recommend for or against the use of OCs solely for the primary prevention of ovarian cancer. Although the net effects of the current patterns of OC use likely result in increased life expectancy when other noncontraceptive benefits are included, the harm/benefit ratio for ovarian cancer prevention alone is uncertain, particularly when the potential quality-of-life impact of breast cancer and vascular events are considered.