Comparative effectiveness and harms of intravitreal antivascular endothelial growth factor agents for three retinal conditions: a systematic review and meta-analysis.

Intravitreal antivascular endothelial growth factor (VEGF) agents are widely used to treat ocular conditions but the benefits and harms of these treatments are uncertain. We conducted a systematic review to compare the effects of aflibercept, bevacizumab and ranibizumab on best-corrected visual acuity (BCVA) changes, quality of life and ocular or systemic adverse events in patients with neovascular age-related macular degeneration (NVAMD), diabetic macular oedema (DME) and central or branch retinal vein occlusion (RVO). We searched published and unpublished literature sources to February 2017 for randomised controlled trials and cohort or modelling studies reporting comparative costs in the USA. Two reviewers extracted data and graded the strength of the evidence using established methods. Of 17 included trials, none reported a clinically important difference (≥ 5 letters) in visual acuity gains between agents. Nine trials provide high-strength evidence of no difference between bevacizumab and ranibizumab for NVAMD. Three trials provide moderate-strength evidence of no difference between bevacizumab and ranibizumab for DME. There was low-strength evidence of similar effects between aflibercept and ranibizumab for NVAMD, aflibercept and bevacizumab for RVO and all three agents for DME. There was insufficient evidence to compare bevacizumab and ranibizumab for RVO. Rates of ocular adverse events were low, and systemic harms were generally similar between groups, although 1 DME trial reported more arterial thrombotic events with ranibizumab versus aflibercept. Overall, no agent had a clear advantage over another for effectiveness or safety. Aflibercept and ranibizumab were significantly less cost-effective than repackaged bevacizumab in two trials. Systematic review registration number: CRD42016034076.

Antithrombotic Strategies After Bioprosthetic Aortic Valve Replacement: A Systematic Review.

BACKGROUND: The optimal antithrombotic regimen after bioprosthetic aortic valve replacement (bAVR) is unclear. We conducted a systematic review of various anticoagulation strategies following surgical or transcatheter bAVR (TAVR). METHODS: We searched Medline, PubMed, Embase, Evidence-Based Medicine Reviews, and gray literature through June 2017 for controlled clinical trials and cohort studies that directly compared different antithrombotic strategies in nonpregnant adults who had undergone bAVR. We assessed risk of bias and graded the strength of the evidence using established methods. RESULTS: Of 4,554 titles reviewed, 6 clinical trials and 13 cohort studies met inclusion criteria. We found moderate-strength evidence that mortality, thromboembolic events, and bleeding rates are similar between aspirin and warfarin after surgical bAVR. Observational data suggest lower mortality and thromboembolic events with aspirin combined with warfarin compared with aspirin alone after surgical bAVR, but the effect size is small and the combination is associated with a substantial increase in bleeding risk. We found insufficient evidence for all other treatment comparisons in surgical bAVR. In TAVR patients, we found moderate-strength evidence that mortality, stroke, and major cardiac events are similar between dual antiplatelet therapy and aspirin alone, though a nonsignificantly lower rate of bleeding occurred with aspirin alone. CONCLUSIONS: Treatment with warfarin or aspirin leads to similar outcomes after surgical bAVR. Combining aspirin with warfarin may lead to a small decrease in thromboembolism and mortality, but is accompanied by increased bleeding. For TAVR patients, aspirin is equivalent to dual antiplatelet therapy for reducing thromboembolism and mortality, with a possible decrease in bleeding.

A systematic review of clinic and community intervention to increase fecal testing for colorectal cancer in rural and low-income populations in the United States - How, what and when?

BACKGROUND: Interventions to improve fecal testing for colorectal cancer (CRC) exist, but are not yet routine practice. We conducted this systematic review to determine how implementation strategies and contextual factors influenced the uptake of interventions to increase Fecal Immunochemical Tests (FIT) and Fecal Occult Blood Testing (FOBT) for CRC in rural and low-income populations in the United States. METHODS: We searched Medline and the Cochrane Library from January 1998 through July 2016, and Scopus and clinicaltrials.gov through March 2015, for original articles of interventions to increase fecal testing for CRC. Two reviewers independently screened abstracts, reviewed full-text articles, extracted data and performed quality assessments. A qualitative synthesis described the relationship between changes in fecal testing rates for CRC, intervention components, implementation strategies, and contextual factors. A technical expert panel of primary care professionals, health system leaders, and academicians guided this work. RESULTS: Of 4218 citations initially identified, 27 unique studies reported in 29 publications met inclusion criteria. Studies were conducted in primary care (n = 20, 74.1%), community (n = 5, 18.5%), or both (n = 2, 7.4%) settings. All studies (n = 27, 100.0%) described multicomponent interventions. In clinic based studies, components that occurred most frequently among the highly effective/effective study arms were provision of kits by direct mail, use of a pre-addressed stamped envelope, client reminders, and provider ordered in-clinic distribution. Interventions were delivered by clinic staff/community members (n = 10, 37.0%), research staff (n = 6, 22.2%), both (n = 10, 37.0%), or it was unclear (n = 1, 3.7%). Over half of the studies lacked information on training or monitoring intervention fidelity (n = 15, 55.6%). CONCLUSIONS: Studies to improve FIT/FOBT in rural and low-income populations utilized multicomponent interventions. The provision of kits through the mail, use of pre-addressed stamped envelopes, client reminders and in-clinic distribution appeared most frequently in the highly effective/effective clinic-based study arms. Few studies described contextual factors or implementation strategies. More robust application of guidelines to support reporting on methods to select, adapt and implement interventions can help end users determine not just which interventions work to improve CRC screening, but which interventions would work best in their setting given specific patient populations, clinical settings, and community characteristics. TRIAL REGISTRATION: In accordance with PRISMA guidelines, our systematic review protocol was registered with PROSPERO, the international prospective register of systematic reviews, on April 16, 2015 (registration number CRD42015019557 ).

The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review.

BACKGROUND: Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain. PURPOSE: To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations. DATA SOURCES: MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017. STUDY SELECTION: Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes. DATA EXTRACTION: Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria. DATA SYNTHESIS: From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient. LIMITATION: Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily. CONCLUSION: Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs. (PROSPERO: CRD42016033623).

Effectiveness of Left Atrial Appendage Exclusion Procedures to Reduce the Risk of Stroke: A Systematic Review of the Evidence.

BACKGROUND: Atrial fibrillation is an important cause of cardioembolic stroke. Oral anticoagulants (OAC) reduce stroke risk but increase the risk of serious bleeding. Left atrial appendage (LAA) procedures have been developed to isolate the LAA from circulating blood flow, as an alternative to OAC. We conducted a systematic review of the benefits and harms of surgical and percutaneous LAA exclusion procedures. METHODS AND RESULTS: We searched multiple data sources, including Ovid MEDLINE, Cochrane, and Embase, through January 7, 2015. Of 2567 citations, 20 primary studies met prespecified inclusion criteria. We abstracted data on patient characteristics, stroke, mortality, and adverse effects. We assessed study quality and graded the strength of evidence using published criteria. Trials found low-strength evidence that percutaneous LAA exclusion confers similar risks of stroke and mortality as continued OAC, but this evidence was limited to the Watchman device in patients eligible for long-term OAC. Observational studies found moderate-strength evidence of serious harms with a variety of percutaneous LAA procedures. There is low-strength evidence that surgical LAA exclusion does not add significant harm during heart surgery for another indication, but evidence on stroke reduction is insufficient. CONCLUSIONS: There is limited evidence that the Watchman device may be noninferior to long-term OAC in selected patients. Data on effectiveness of LAA exclusion devices is lacking in patients ineligible for long-term OAC. Percutaneous LAA devices are associated with high rates of procedure-related harms. Although surgical LAA exclusion during heart surgery does not seem to add incremental harm, there is insufficient evidence of benefit.

Screening for hepatocellular carcinoma in chronic liver disease: a systematic review.

BACKGROUND: Guidelines recommend routine screening for hepatocellular carcinoma (HCC) in high-risk patients, but the strength of evidence supporting these recommendations is unclear. PURPOSE: To review the benefits and harms of HCC screening in patients with chronic liver disease. DATA SOURCES: MEDLINE, PsycINFO, and ClinicalTrials.gov from inception to April 2014; Cochrane databases to June 2013; reference lists; and technical advisors. STUDY SELECTION: English-language trials and observational studies comparing screening versus no screening, studies of harms, and trials comparing different screening intervals. DATA EXTRACTION: Mortality and adverse events were the outcomes of interest. Individual-study quality and the overall strength of evidence were dual-reviewed using published criteria. DATA SYNTHESIS: Of 13,801 citations, 22 studies met inclusion criteria. The overall strength of evidence on the effects of screening was very low. One large trial of patients with hepatitis B found decreased HCC mortality with periodic ultrasonographic screening (rate ratio, 0.63 [95% CI, 0.41 to 0.98]), but the study was limited by methodological flaws. Another trial in patients with hepatitis B found no survival benefit with periodic α-fetoprotein screening. In 18 observational studies, screened patients had earlier-stage HCC than clinically diagnosed patients, but lead- and length-time biases confounded the effects on mortality. Two trials found no survival differences between shorter (3- to 4-month) and longer (6- to 12-month) screening intervals. Harms of screening were not well-studied. LIMITATIONS: Only English-language studies were included. The evidence base is limited by methodological issues and a paucity of trials. CONCLUSION: There is very-low-strength evidence about the effects of HCC screening on mortality in patients with chronic liver disease. Screening tests can identify early-stage HCC, but whether systematic screening leads to a survival advantage over clinical diagnosis is uncertain. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs Quality Enhancement Research Initiative.

Treatment of anemia in patients with heart disease: a systematic review.

BACKGROUND: The benefits of anemia treatment in patients with heart disease are uncertain. PURPOSE: To evaluate the benefits and harms of treatments for anemia in adults with heart disease. DATA SOURCES: MEDLINE, EMBASE, and Cochrane databases; clinical trial registries; reference lists; and technical advisors. STUDY SELECTION: English-language trials of blood transfusions, iron, or erythropoiesis-stimulating agents in adults with anemia and congestive heart failure or coronary heart disease and observational studies of transfusion. DATA EXTRACTION: Data on study design, population characteristics, hemoglobin levels, and health outcomes were extracted. Trials were assessed for quality. DATA SYNTHESIS: Low-strength evidence from 6 trials and 26 observational studies suggests that liberal transfusion protocols do not improve short-term mortality rates compared with less aggressive protocols (combined relative risk among trials, 0.94 [95% CI, 0.61 to 1.42]; I2 = 16.8%), although decreased mortality rates occurred in a small trial of patients with the acute coronary syndrome (1.8% vs. 13.0%; P = 0.032). Moderate-strength evidence from 3 trials of intravenous iron found improved short-term exercise tolerance and quality of life in patients with heart failure. Moderate- to high-strength evidence from 17 trials of erythropoiesis-stimulating agent therapy found they offered no consistent benefits, but their use may be associated with harms, such as venous thromboembolism. LIMITATIONS: Few trials have examined transfusions in patients with heart disease, and observational studies are potentially confounded by indication. Data supporting iron use come mainly from 1 large trial, and long-term effects are unknown. CONCLUSION: Higher transfusion thresholds do not consistently improve mortality rates, but large trials are needed. Intravenous iron may help to alleviate symptoms in patients with heart failure and iron deficiency and also warrants further study. Erythropoiesis-stimulating agents do not seem to benefit patients with mild to moderate anemia and heart disease and may be associated with serious harms. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force.

BACKGROUND: Traditional risk factors do not explain all of the risk for incident coronary heart disease (CHD) events. Various new or emerging risk factors have the potential to improve global risk assessment for CHD. PURPOSE: To summarize the results of 9 systematic reviews of novel risk factors to help the U.S. Preventive Services Task Force (USPSTF) evaluate the factors' clinical usefulness. DATA SOURCES: Results from a MEDLINE search for English-language articles published from 1966 to September 2008, using the Medical Subject Heading terms cohort studies and cardiovascular diseases in combination with terms for each risk factor. STUDY SELECTION: Studies were included if the participants had no baseline cardiovascular disease and the investigators adjusted for at least 6 Framingham risk factors. DATA EXTRACTION: Study quality was evaluated by using USPSTF criteria and overall quality of evidence for each risk factor by using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation framework. Each factor's potential clinical value was evaluated by using a set of criteria that emphasized the importance of the effect of that factor on the reclassification of intermediate-risk persons. DATA SYNTHESIS: 9 systematic reviews were conducted. C-reactive protein (CRP) was the best candidate for use in screening and the most rigorously studied, but evidence that changes in CRP level lead to primary prevention of CHD events is inconclusive. The other evaluated risk factors were coronary artery calcium score as measured by electron-beam computed tomography, lipoprotein(a) level, homocysteine level, leukocyte count, fasting blood glucose, periodontal disease, ankle-brachial index, and carotid intima-media thickness. The availability and validity of the evidence varied considerably across the risk factors in terms of aggregate quality, consistency of findings, and applicability to intermediate-risk persons in the general population. For most risk factors, no studies assessed their usefulness for reclassifying intermediate-risk persons. LIMITATIONS: Because of lack of access to original data, no firm conclusions could be drawn about differences in risk prediction among racial and ethnic groups. The review did not emphasize within-cohort comparisons of multiple risk factors. CONCLUSION: The current evidence does not support the routine use of any of the 9 risk factors for further risk stratification of intermediate-risk persons.

Evidence on the benefits and harms of screening and treating pregnant women who are asymptomatic for bacterial vaginosis: an update review for the U.S. Preventive Services Task Force.

BACKGROUND: Bacterial vaginosis is the most common lower genital tract syndrome among women of reproductive age. There has been continued debate about the value of screening and treating asymptomatic pregnant women for bacterial vaginosis. PURPOSE: To examine new evidence on the benefits and harms of screening and treating bacterial vaginosis in asymptomatic pregnant women. DATA SOURCES: English-language studies on Ovid MEDLINE (2000 to September 2007) and Cochrane Library databases (through September 2007), reference lists, and expert suggestions. STUDY SELECTION: Screening, treatment, or adverse effect studies with pregnancy outcome data in women who are asymptomatic for bacterial vaginosis. DATA EXTRACTION: Study and patient characteristics, treatment variables, adverse pregnancy outcomes, and internal validity quality criteria from the U.S. Preventive Services Task Force (USPSTF) and Jadad scale were abstracted. DATA SYNTHESIS: 7 new randomized, controlled treatment trials and 2001 report data were combined in a series of meta-analyses to estimate the pooled effect of treatment on preterm delivery (<37, <34, and <32 weeks); low birthweight; and preterm, premature rupture of membranes. LIMITATIONS: No screening studies that compared a screened population with a nonscreened population were found. Significant heterogeneity was found among the high-risk treatment trials (P < 0.001). It is not clear from the detailed description of the studies which factors explain the differences in preterm delivery rates and potentially the association of treatment effect; however, both raise concern for the unintended potential for harm. CONCLUSION: No benefit was found in treating women with low- or average-risk pregnancies for asymptomatic bacterial vaginosis. More research is needed to better understand these groups and the conditions under which treatment can be harmful or helpful, and to explore the relevance of bacterial vaginosis to other adverse pregnancy outcomes, such as delivery before 34 weeks.

Racial and ethnic disparities in the VA health care system: a systematic review.

OBJECTIVES: To better understand the causes of racial disparities in health care, we reviewed and synthesized existing evidence related to disparities in the "equal access" Veterans Affairs (VA) health care system. METHODS: We systematically reviewed and synthesized evidence from studies comparing health care utilization and quality by race within the VA. RESULTS: Racial disparities in the VA exist across a wide range of clinical areas and service types. Disparities appear most prevalent for medication adherence and surgery and other invasive procedures, processes that are likely to be affected by the quantity and quality of patient-provider communication, shared decision making, and patient participation. Studies indicate a variety of likely root causes of disparities including: racial differences in patients' medical knowledge and information sources, trust and skepticism, levels of participation in health care interactions and decisions, and social support and resources; clinician judgment/bias; the racial/cultural milieu of health care settings; and differences in the quality of care at facilities attended by different racial groups. CONCLUSIONS: Existing evidence from the VA indicates several promising targets for interventions to reduce racial disparities in the quality of health care.

Screening for elevated lead levels in childhood and pregnancy: an updated summary of evidence for the US Preventive Services Task Force.

BACKGROUND: In 1996, the US Preventive Services Task Force provided recommendations for routine screening of asymptomatic children and pregnant women for elevated blood lead levels. This review updates the evidence for the benefits and harms of screening and intervention for elevated blood lead in asymptomatic children and pregnant women. METHODS: We searched Medline, reference lists of review articles, and tables of contents of leading pediatric journals for studies published in 1995 or later that contained new information about the prevalence, diagnosis, natural course, or treatment of elevated lead levels in asymptomatic children aged 1 to 5 years and pregnant women. RESULTS: The prevalence of elevated blood lead levels among children and women in the United States, like that in the general population, continues to decline sharply, primarily because of marked reductions in environmental exposure, but still varies substantially among different communities and populations. Similar to the findings in 1996, our searches did not identify direct evidence from controlled studies that screening children for elevated blood lead levels results in improved health outcomes, and there was no direct evidence identified from controlled studies that screening improves pregnancy or perinatal outcomes. No new relevant information regarding the accuracy of screening for lead toxicity was identified during the update, and we did not identify evidence that demonstrates that universal screening for blood lead results in better clinical outcomes than targeted screening. Substantial new relevant information regarding the adverse effects of screening and interventions was not identified. CONCLUSIONS: There is no persuasive evidence that screening for elevated lead levels in asymptomatic children will improve clinical outcomes. For those children who are screened and found to have elevated levels, there is conflicting evidence demonstrating the clinical effectiveness of early detection and intervention.