Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

BACKGROUND: The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. OBJECTIVES: To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, Global Index Medicus, Global Health, and Scopus from inception on March 2023, and monitored the literature monthly. We updated the search strategies with new terms and added the database Global Index Medicus in lieu of LILACS. SELECTION CRITERIA: We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). DATA COLLECTION AND ANALYSIS: One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. MAIN RESULTS: We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (OR 1.00, 95% CI 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with BMI under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. AUTHORS' CONCLUSIONS: There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. We noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception: a Cochrane systematic review.

BACKGROUND: The coronavirus disease COVID-19 is associated with an increased risk of thrombotic events. Individuals with COVID-19 using hormonal contraception could be at additional risk for thromboembolism, but evidence is sparse. METHODS: We conducted a systematic review on the risk of thromboembolism with hormonal contraception use in women aged 15-51 years with COVID-19. We searched multiple databases through March 2022, including all studies comparing outcomes of patients with COVID-19 using or not using hormonal contraception. We applied standard risk of bias tools to evaluate studies and GRADE methodology to assess certainty of evidence. Our primary outcomes were venous and arterial thromboembolism. Secondary outcomes included hospitalisation, acute respiratory distress syndrome, intubation, and mortality. RESULTS: Of 2119 studies screened, three comparative non-randomised studies of interventions (NRSIs) and two case series met the inclusion criteria. All studies had serious to critical risk of bias and low study quality. Overall, there may be little to no effect of combined hormonal contraception (CHC) use on odds of mortality for COVID-19-positive patients (OR 1.0, 95% CI 0.41 to 2.4). The odds of hospitalisation for COVID-19-positive CHC users may be slightly decreased compared with non-users for patients with body mass index <35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97). Use of any type of hormonal contraception may have little to no effect on hospitalisation rates for COVID-19-positive individuals (OR 0.99, 95% CI 0.68 to 1.44). CONCLUSIONS: Not enough evidence exists to draw conclusions regarding risk of thromboembolism in patients with COVID-19 using hormonal contraception. Evidence suggests there may be little to no or slightly decreased odds of hospitalisation, and little to no effect on odds of mortality for hormonal contraception users versus non-users with COVID-19.

Risk of thromboembolism in patients with COVID-19 who are using hormonal contraception.

BACKGROUND: The novel coronavirus disease (COVID-19) has led to significant mortality and morbidity, including a high incidence of related thrombotic events. There has been concern regarding hormonal contraception use during the COVID-19 pandemic, as this is an independent risk factor for thrombosis, particularly with estrogen-containing formulations. However, higher estrogen levels may be protective against severe COVID-19 disease. Evidence for risks of hormonal contraception use during the COVID-19 pandemic is sparse. We therefore conducted a living systematic review that will be updated as new data emerge on the risk of thromboembolism with hormonal contraception use in patients with COVID-19. OBJECTIVES: To determine if use of hormonal contraception increases risk of venous and arterial thromboembolism in women with COVID-19. To determine if use of hormonal contraception increases other markers of COVID-19 severity including hospitalization in the intensive care unit, acute respiratory distress syndrome, intubation, and mortality. A secondary objective is to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: ⁠⁠⁠⁠⁠⁠We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Global Health, and Scopus from inception to search update in March 2022. For the living systematic review, we monitored the literature monthly. SELECTION CRITERIA: We included all published and ongoing studies of patients with COVID-19 comparing outcomes of those on hormonal contraception versus those not on hormonal contraception. This included case series and non-randomized studies of interventions (NRSI). DATA COLLECTION AND ANALYSIS: One review author extracted study data and this was checked by a second author. Two authors individually assessed risk of bias for the comparative studies using the ROBINS-I tool and a third author helped reconcile differences. For the living systematic review, we will publish updates to our synthesis every six months. In the event that we identify a study with a more rigorous study design than the current included evidence prior to the planned six-month update, we will expedite the synthesis publication. MAIN RESULTS: We included three comparative NRSIs with 314,704 participants total and two case series describing 13 patients. The three NRSIs had serious to critical risk of bias in several domains and low study quality. Only one NRSI ascertained current use of contraceptives based on patient report; the other two used diagnostic codes within medical records to assess hormonal contraception use, but did not confirm current use nor indication for use. None of the NRSIs included thromboembolism as an outcome. Studies were not similar enough in terms of their outcomes, interventions, and study populations to combine with meta-analyses. We therefore narratively synthesized all included studies. Based on results from one NRSI, there may be little to no effect of combined hormonal contraception use on odds of mortality for COVID-19 positive patients (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.41 to 2.40; 1 study, 18,892 participants; very low-certainty evidence). Two NRSIs examined hospitalization rates for hormonal contraception users versus non-users. Based on results from one NRSI, the odds of hospitalization for COVID-19 positive combined hormonal contraception users may be slightly decreased compared with non-users for patients with body mass index (BMI) under 35 kg/m2 (OR 0.79, 95% CI 0.64 to 0.97; 1 study, 295,689 participants; very low-certainty evidence). According to results of the other NRSI assessing use of any type of hormonal contraception, there may be little to no effect on hospitalization rates for COVID-19 positive individuals (OR 0.99, 95% CI 0.68 to 1.44; 1 study, 123 participants; very low-certainty evidence). We included two case series because no comparative studies directly assessed thromboembolism as an outcome. In a case series of six pediatric COVID-19 positive patients with pulmonary embolism, one (older than 15 years of age) was using combined hormonal contraception. In a second case series of seven COVID-19 positive patients with cerebral venous thrombosis, one was using oral contraceptives. One comparative study and one case series reported on intubation rates, but the evidence for both is very uncertain. In the comparative study of 123 COVID-19 positive patients (N = 44 using hormonal contraception and N = 79 not using hormonal contraception), no patients in either group required intubation. In the case series of seven individuals with cerebral venous thromboembolism, one oral contraceptive user and one non-user required intubation. AUTHORS' CONCLUSIONS: There are no comparative studies assessing risk of thromboembolism in COVID-19 patients who use hormonal contraception, which was the primary objective of this review. Very little evidence exists examining the risk of increased COVID-19 disease severity for combined hormonal contraception users compared to non-users of hormonal contraception, and the evidence that does exist is of very low certainty. The odds of hospitalization for COVID-19 positive users of combined hormonal contraceptives may be slightly decreased compared with those of hormonal contraceptive non-users, but the evidence is very uncertain as this is based on one study restricted to patients with BMI under 35 kg/m2. There may be little to no effect of combined hormonal contraception use on odds of intubation or mortality among COVID-19 positive patients, and little to no effect of using any type of hormonal contraception on odds of hospitalization and intubation for COVID-19 patients. At a minimum, we noted no large effect for risk of increased COVID-19 disease severity among hormonal contraception users. We specifically noted gaps in pertinent data collection regarding hormonal contraception use such as formulation, hormone doses, and duration or timing of contraceptive use. Differing estrogens may have different thrombogenic potential given differing potency, so it would be important to know if a formulation contained, for example, ethinyl estradiol versus estradiol valerate. Additionally, we downgraded several studies for risk of bias because information on the timing of contraceptive use relative to COVID-19 infection and method adherence were not ascertained. No studies reported indication for hormonal contraceptive use, which is important as individuals who use hormonal management for medical conditions like heavy menstrual bleeding might have different risk profiles compared to individuals using hormones for contraception. Future studies should focus on including pertinent confounders like age, obesity, history of prior venous thromboembolism, risk factors for venous thromboembolism, and recent pregnancy.

Adjunct interventions to standard medical management of buprenorphine in outpatient settings: A systematic review of the evidence.

BACKGROUND: A growing body of research has examined adjunctive interventions supportive of engagement and retention in treatment among patients receiving buprenorphine for opioid use disorder (OUD). We conducted a systematic review of the literature addressing the effect on key outcomes of adjunctive interventions provided alongside standard medical management of buprenorphine in outpatient settings. METHODS: We included prospective studies examining adults receiving buprenorphine paired with an adjunctive intervention for the treatment of OUD in an outpatient setting. Data sources included Medline, Cochrane Central Register of Controlled Trials, CINAHL and PsycINFO from inception through January 2020. Two raters independently reviewed full-text articles, abstracted data and appraised risk of bias. Outcomes examined included abstinence, retention in treatment and non-addiction-related health outcomes. RESULTS: The final review includes 20 manuscripts, 11 randomized control trials (RCTs), three secondary analyses of RCTs and six observational studies. Most studies examined psychosocial interventions (n = 14). Few examined complementary therapies (e.g., yoga; n = 2) or technological interventions (e.g., electronic pill dispensation; n = 3); one study examined an intervention addressing structural barriers to care (patient navigators; n = 1). Low risk of bias RCTs found no evidence that adding psychosocial interventions to buprenorphine treatment improves substance use outcomes. CONCLUSIONS: Research is needed to identify adjunctive interventions with potential to support medication adherence and addiction-related outcomes for patients engaged in buprenorphine treatment. Data from clinical trials suggest that lack of ready access to psychosocial treatments should not discourage clinicians from prescribing buprenorphine.

A prospective comparison of evidence synthesis search strategies developed with and without text-mining tools.

OBJECTIVE: We compared the process of developing searches with and without using text-mining tools (TMTs) for evidence synthesis products. STUDY DESIGN: This descriptive comparative analysis included seven systematic reviews, classified as simple or complex. Two librarians created MEDLINE strategies for each review, using either usual practice (UP) or TMTs. For each search we calculated sensitivity, number-needed-to-read (NNR) and time spent developing the search strategy. RESULTS: We found UP searches were more sensitive (UP 92% (95% CI, 85-99); TMT 84.9% (95% CI, 74.4-95.4)), with lower NNR (UP 83 (SD 34); TMT 90 (SD 68)). UP librarians spent an average of 12 h (SD 8) developing search strategies, compared to TMT librarians' 5 hours (SD 2). CONCLUSION: Across all reviews, TMT searches were less sensitive than UP searches, but confidence intervals overlapped. For simple SR topics, TMT searches were faster and slightly less sensitive than UP. For complex SR topics, TMT searches were faster and less sensitive than UP searches but identified unique eligible citations not found by the UP searches.

Antibody Response After SARS-CoV-2 Infection and Implications for Immunity : A Rapid Living Review.

BACKGROUND: The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear. PURPOSE: To synthesize evidence on the prevalence, levels, and durability of detectable antibodies after SARS-CoV-2 infection and whether antibodies to SARS-CoV-2 confer natural immunity. DATA SOURCES: MEDLINE (Ovid), Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, World Health Organization global literature database, and Covid19reviews.org from 1 January through 15 December 2020, limited to peer-reviewed publications available in English. STUDY SELECTION: Primary studies characterizing the prevalence, levels, and duration of antibodies in adults with SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR); reinfection incidence; and unintended consequences of antibody testing. DATA EXTRACTION: Two investigators sequentially extracted study data and rated quality. DATA SYNTHESIS: Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection with SARS-CoV-2 and that IgG levels peak approximately 25 days after symptom onset and may remain detectable for at least 120 days. Moderate-strength evidence suggests that IgM levels peak at approximately 20 days and then decline. Low-strength evidence suggests that most adults generate neutralizing antibodies, which may persist for several months like IgG. Low-strength evidence also suggests that older age, greater disease severity, and presence of symptoms may be associated with higher antibody levels. Some adults do not develop antibodies after SARS-CoV-2 infection for reasons that are unclear. LIMITATIONS: Most studies were small and had methodological limitations; studies used immunoassays of variable accuracy. CONCLUSION: Most adults with SARS-CoV-2 infection confirmed by RT-PCR develop antibodies. Levels of IgM peak early in the disease course and then decline, whereas IgG peaks later and may remain detectable for at least 120 days. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).

Biological measures and diagnostic tools for Gulf War Illness - A systematic review.

AIMS: Gulf War Illness (GWI) is a chronic multisymptom illness with debated etiology and pathophysiology. This systematic review catalogues studies of validated biological tests for diagnosing GWI and of associations between biological measures and GWI for their promise as biomarkers. MAIN METHODS: We searched multiple sources through February 2020 for studies of diagnostic tests of GWI and of associations between biological measures and GWI. We abstracted data on study design, demographics, and outcomes. We assessed the risk of bias of included studies. KEY FINDINGS: We did not identify any studies validating tests of biomarkers that distinguish cases of GWI from non-cases. We included the best-fitting studies, 32 completed and 24 ongoing or unpublished studies, of associations between GWI and biological measures. The less well-fitting studies (n = 77) were included in a Supplementary Table. Most studies were of the central nervous and immune systems and indicated a significant association of the biological measure with GWI case status. Biological measures were heterogeneous across studies. SIGNIFICANCE: Our review indicates that there are no existing validated biological tests to determine GWI case status. Many studies have assessed the potential association between a variety of biological measures and GWI, the majority of which pertain to the immune and central nervous systems. More importantly, while most studies indicated a significant association between biological measures and GWI case status, the biological measures across studies were extremely heterogeneous. Due to the heterogeneity, the focus of the review is to map out what has been examined, rather than synthesize information.

Retention Strategies for Medications for Opioid Use Disorder in Adults: A Rapid Evidence Review.

OBJECTIVES: Although medications for opioid use disorder (MOUD) save lives, treatment retention remains challenging. Identification of interventions to improve MOUD retention is of interest to policymakers and researchers. On behalf of the Agency for Healthcare Research and Quality, we conducted a rapid evidence review on interventions to improve MOUD retention. METHODS: We searched MEDLINE and the Cochrane Library from February 2009 through August 2019 for systematic reviews and randomized trials of care settings, services, logistical support, contingency management, health information technology (IT), extended-release (XR) formulations, and psychosocial interventions that assessed retention at least 3 months. RESULTS: Two systematic reviews and 39 primary studies were included; most did not focus on retention as the primary outcome. Initiating MOUD in soon-to-be-released incarcerated people improved retention following release. Contingency management may improve retention using antagonist but not agonist MOUD. Retention with interventions integrating medical, psychiatric, social services, or IT did not differ from in-person treatment-as-usual approaches. Retention was comparable with XR- compared to daily buprenorphine formulations and conflicting with XR-naltrexone monthly injection compared to daily buprenorphine. Most psychosocial interventions did not improve retention. DISCUSSION: Consistent but sparse evidence supports criminal justice prerelease MOUD initiation, and contingency management interventions for antagonist MOUD. Integrating MOUD with medical, psychiatric, social services, delivering through IT, or administering via XR-MOUD formulations did not worsen retention. Fewer than half of the studies we identified focused on retention as a primary outcome. Studies used different measures of retention, making it difficult to compare effectiveness. Additional inquiry into the causes of low retention would inform future interventions.Registration: PROSPERO: CRD42019134739.

A Systematic Review of Therapeutic Interventions and Management Strategies for Gulf War Illness.

INTRODUCTION: After the 1990 to 1991 conflict in the Persian Gulf, many Gulf War Veterans began reporting numerous unexplained symptoms including, but not limited to, systemic pain, fatigue, flu-like symptoms, and difficulty with memory/concentration. These symptom clusters are now referred to as Gulf War Illness (GWI). Although the etiology of GWI is still debated, as many as 250,000 former service members have been continually suffering from GWI since 1991, making the need for treatment urgent. A broad variety of treatments have been considered for GWI, but there has not been a broad and comprehensive assessment of what is known and not known about GWI treatment. We conducted a systematic review to catalogue the types of treatments that have been examined for GWI, to evaluate the effectiveness and harms of these interventions, and to identify promising and ongoing areas of future GWI treatment research. MATERIALS AND METHODS: We searched electronic databases, trial registries, and reference lists through September 2019 for randomized controlled trial and nonrandomized controlled trial and cohort studies directly comparing interventions for Veterans with GWI to each other, placebo, or usual care. We abstracted data on study design, demographics, interventions, and outcomes. Two reviewers independently assessed studies for inclusion, quality, and strength of evidence (SOE) using prespecified criteria. We resolved discordant ratings by discussion and consensus. RESULTS: We identified 12 randomized controlled trials, each of which examined a different intervention for GWI. We found moderate SOE that cognitive behavioral therapy and exercise, separately and in combination, were associated with improvements in several GWI symptom domains. There was low SOE of benefit from two mindfulness-based interventions and continuous positive airway pressure (CPAP). Mindfulness-based stress reduction improved pain, cognitive functioning, fatigue, depression, and posttraumatic stress disorder (PTSD), whereas mind-body bridging improved fatigue, depression, posttraumatic stress disorder, and sleep, although pain and other outcomes did not improve. Continuous positive airway pressure improved overall physical health, pain, cognitive functioning, fatigue, mental health, and sleep quality in a small study of Veterans with sleep-disordered breathing and GWI. We found moderate SOE that doxycycline is ineffective for GWI in mycoplasma DNA-positive Veterans and increases the risk of adverse events compared with placebo. We also found 33 ongoing, single-arm pilot, or unpublished studies examining a variety of interventions. CONCLUSION: Cognitive behavioral therapy (moderate SOE), exercise (moderate SOE), and mindfulness-based interventions (low SOE) may be effective in improving several symptom domains in patients with GWI. Doxycycline was ineffective and associated with harms (moderate SOE). Larger, more rigorous studies are needed to confirm the benefits found in completed trials. A wide array of treatments are being assessed in ongoing trials. A sufficient evidence base will need to be developed to guide clinicians about which treatments are most likely to be effective in clinical practice and which treatments should be avoided.

A systematic review and meta-analysis of medications for stimulant use disorders in patients with co-occurring opioid use disorders.

BACKGROUND: Stimulant (cocaine and/or methamphetamine) use has increased among people with opioid use disorder. We conducted a systematic review of medications for stimulant use disorders in this population. METHODS: We searched for randomized controlled trials in multiple databases through April 2019, and dual-screened studies using pre-specified inclusion criteria. Primary outcomes were abstinence defined as stimulant-negative urine screens for ≥3 consecutive weeks; overall use as the proportion of stimulant-negative urine specimens; and retention as the proportion of participants who completed treatment. We rated strength of evidence using established criteria and conducted meta-analyses of comparable interventions and outcomes. RESULTS: Thirty-four trials of 22 medications focused on cocaine use disorder in patients with opioid use disorder. Most studies enrolled participants stabilized on opioid maintenence therapy, generally methadone. None of the six studies that assessed abstinence found significant differences between groups. We found moderate-strength evidence that antidepressants (desipramine, bupropion, and fluoxetine) worsened retention. There was moderate-strength evidence that disulfiram worsened treatment retention (N = 605, RR 0.86, 95 % CI 0.77 to 0.95). We found low-strength evidence that psychostimulants (mazindol and dexamphetamine) may reduce cocaine use, though the difference was not statistically significant (standard mean difference 0.35 [95 % CI -0.05 to 0.74]). There was only 1 trial for methamphetamine use disorder, which showed insufficient-strength evidence for naltrexone. CONCLUSIONS: Co-occurring stimulant/opioid use disorder is an important problem for targeting future research. Medication trials for methamphetamine use disorder are lacking in this population. Most of the medications studied for cocaine use were ineffective, although psychostimulants warrant further study.

Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis.

AIMS: Addiction to methamphetamine/amphetamine (MA/A) is a major public health problem. Currently there are no pharmacotherapies for MA/A use disorder that have been approved for use by the US Food and Drug Administration or the European Medicines Agency. We reviewed the effectiveness of pharmacotherapy for MA/A use disorder to assess the quality, publication bias and overall strength of the evidence. METHODS: Systematic review and meta-analysis. We searched multiple data sources (MEDLINE, PsycINFO and Cochrane Library) to April 2019 for systematic reviews (SRs) and randomized controlled trials (RCTs). Included studies recruited adults who had MA/A use disorder; sample sizes ranged from 19 to 229 participants. Outcomes of interest were abstinence, defined as 3 or more consecutive weeks with negative urine drug screens (UDS); overall use, analyzed as the proportion of MA/A negative UDS specimens; and treatment retention. One SR of pharmacotherapies for MA/A use disorder and 17 additional RCTs met our inclusion criteria encompassing 17 different drugs (antidepressants, antipsychotics, psychostimulants, anticonvulsants and opioid antagonists). We combined the findings of trials with comparable interventions and outcome measures in random-effects meta-analyses. We assessed quality, publication bias and the strength of evidence for each outcome using standardized criteria. RESULTS: There was low-strength evidence from two RCTs that methylphenidate may reduce MA/A use: 6.5 versus 2.8% MA/A-negative UDS in one study (n = 34, P = 0.008) and 23 versus 16% in another study (n = 54, P = 0.047). Antidepressants as a class had no statistically significant effect on abstinence or retention on the basis of moderate strength evidence. Studies of anticonvulsants, antipsychotics (aripiprazole), opioid antagonists (naltrexone), varenicline and atomoxetine provided either low-strength or insufficient evidence of no effect on the outcomes of interest. Many of the studies had high or unclear risk of bias. CONCLUSIONS: On the basis of low- to moderate-strength evidence, most medications evaluated for methamphetamine/amphetamine use disorder have not shown a statistically significant benefit. However, there is low-strength evidence that methylphenidate may reduce use.

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.

Rapid Evidence Review of Mobile Applications for Self-management of Diabetes.

BACKGROUND: Patients with diabetes lack information on which commercially available applications (apps) improve diabetes-related outcomes. We conducted a rapid evidence review to examine features, clinical efficacy, and usability of apps for self-management of type 1 and type 2 diabetes in adults. METHODS: Ovid/Medline and the Cochrane Database of Systematic Reviews were searched for systematic reviews and technology assessments. Reference lists of relevant systematic reviews were examined for primary studies. Additional searches for primary studies were conducted online, through Ovid/Medline, Embase, CINAHL, and ClinicalTrials.gov . Studies were evaluated for eligibility based on predetermined criteria, data were extracted, study quality was assessed using a risk of bias tool, information on app features was collected, and app usability was assessed. Results are summarized qualitatively. RESULTS: Fifteen articles evaluating 11 apps were identified: six apps for type 1 and five apps for type 2 diabetes. Common features of apps included setting reminders and tracking blood glucose and hemoglobin A1c (HbA1c), medication use, physical activity, and weight. Compared with controls, use of eight apps, when paired with support from a healthcare provider or study staff, improved at least one outcome, most often HbA1c. Patients did not experience improvements in quality of life, blood pressure, or weight, regardless of app used or type of diabetes. Study quality was variable. Of the eight apps available for usability testing, two were scored "acceptable," three were "marginal," and three were "not acceptable." DISCUSSION: Limited evidence suggests that use of some commercially available apps, when combined with additional support from a healthcare provider or study staff, may improve some short-term diabetes-related outcomes. The impact of these apps on longer-term outcomes is unclear. More rigorous and longer-term studies of apps are needed. REGISTRATION: This review was funded by the Agency for Healthcare Research and Quality (AHRQ). The protocol is available at: http://www.effectivehealthcare.ahrq.gov/topics/diabetes-mobile-devices/research-protocol .

Health Disparities in Veterans: A Map of the Evidence.

BACKGROUND: Goals for improving the quality of care for all Veterans and eliminating health disparities are outlined in the Veterans Health Administration Blueprint for Excellence, but the degree to which disparities in utilization, health outcomes, and quality of care affect Veterans is not well understood. OBJECTIVES: To characterize the research on health care disparities in the Veterans Health Administration by means of a map of the evidence. RESEARCH DESIGN: We conducted a systematic search for research studies published from 2006 to February 2016 in MEDLINE and other data sources. We included studies of Veteran populations that examined disparities in 3 outcome categories: utilization, quality of health care, and patient health. MEASURES: We abstracted data on study design, setting, population, clinical area, outcomes, mediators, and presence of disparity for each outcome category. We grouped the data by population characteristics including race, disability status, mental illness, demographics (age, era of service, rural location, and distance from care), sex identity, socioeconomic status, and homelessness, and created maps illustrating the evidence. RESULTS: We reviewed 4249 citations and abstracted data from 351 studies which met inclusion criteria. Studies examining disparities by race/ethnicity comprised by far the vast majority of the literature, followed by studies examining disparities by sex, and mental health condition. Very few studies examined disparities related to lesbian, gay, bisexual, or transgender identity or homelessness. Disparities findings vary widely by population and outcome. CONCLUSIONS: Our evidence maps provide a "lay of the land" and identify important gaps in knowledge about health disparities experienced by different Veteran populations.

Benefits and Harms of Plant-Based Cannabis for Posttraumatic Stress Disorder: A Systematic Review.

BACKGROUND: Cannabis is available from medical dispensaries for treating posttraumatic stress disorder (PTSD) in many states of the union, yet its efficacy in treating PTSD symptoms remains uncertain. PURPOSE: To identify ongoing studies and review existing evidence regarding the benefits and harms of plant-based cannabis preparations in treating PTSD in adults. DATA SOURCES: MEDLINE, the Cochrane Library, and other sources from database inception to March 2017. STUDY SELECTION: English-language systematic reviews, trials, and observational studies with a control group that reported PTSD symptoms and adverse effects of plant-based cannabis use in adults with PTSD. DATA EXTRACTION: Study data extracted by 1 investigator was checked by a second reviewer; 2 reviewers independently assessed study quality, and the investigator group graded the overall strength of evidence by using standard criteria. DATA SYNTHESIS: Two systematic reviews, 3 observational studies, and no randomized trials were found. The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms. The observational studies found that compared with nonuse, cannabis did not reduce PTSD symptoms. Studies had medium and high risk of bias, and overall evidence was judged insufficient. Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are ongoing and are expected to be completed within 3 years. LIMITATION: Very scant evidence with medium to high risk of bias. CONCLUSION: Evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide important results. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016033623).

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).