Advanced Search

Completed Systematic Reviews




Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults


Public Project Complete

Statistics: 21 Studies, 2 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Objective. To assess select adverse events of antidepressants in the treatment of major depressive disorder (MDD) in adults 65 years old or older. Antidepressants included in this review, as determined by expert opinion, are selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone and vortioxetine. Data sources. MEDLINE®, Embase®, Cochrane Central, and PsycINFO bibliographic databases from earliest date through May 15, 2018; hand searches of references of relevant studies; www.clinicaltrials.gov and the International Controlled Trials Registry Platform. Review methods. Two investigators screened abstracts and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence (SOE) for each comparison and select outcomes. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings. Results. Nineteen RCTs and two observational studies reported in 41 articles were included. Studies mostly evaluated treatment of the acute phase (<12 weeks) of MDD which was of moderate severity in patients 65 years and older, required subjects to be free from uncontrolled medical comorbidities or psychological conditions, and relied on spontaneous reporting of adverse events. Evidence was scarce and conclusions (based on statistical significance) for a given comparison and outcome are based often on a single study; particularly for specific adverse events. None of the RCTs were powered or designed to capture adverse events and most RCTs studied low doses of antidepressants. Observational data were limited by residual confounding. SSRIs (escitalopram and fluoxetine, moderate SOE), vortioxetine (high SOE) and bupropion XR (moderate SOE) led to a statistically similar frequency of adverse events compared with placebo; whereas SNRIs (duloxetine and venlafaxine) were found to cause a greater number of adverse events (high SOE, NNH 10) compared with placebo during treatment of the acute phase of MDD. Both SSRIs (citalopram, escitalopram and fluoxetine) and SNRIs caused a greater number of withdrawals due to adverse events compared with placebo (SSRIs low SOE, NNH 11; SNRIs moderate SOE, NNH 17). Duloxetine led to a greater number of falls compared with placebo (moderate SOE, NNH 10) during 24 weeks treatment. A single observational study provided evidence on long term use of antidepressants (low SOE) and suggested increased risk of adverse events (SSRIs), falls (SSRIs, SNRI venlafaxine, mirtazapine, trazadone), fractures (SSRIs, SNRI venlafaxine, mirtazapine), and mortality (SSRIs, SNRI venlafaxine, mirtazapine, trazadone), compared to no antidepressant. Evidence for the comparative harms of different antidepressants was limited to single RCTs mostly studying treatment of the acute phase of MDD (<12 weeks). Comparing SSRIs to each other or SSRIs to SNRIs showed statistically similar rates of adverse events (moderate SOE). SSRIs (paroxetine, citalopram, sertraline) had fewer withdrawals due to adverse events compared with TCAs (amitriptyline or nortriptyline) (low SOE, NNT 13) as did mirtazapine compared with paroxetine (low SOE, NNT 9). Vortioxetine had fewer adverse events compared with duloxetine (high SOE, NNT 6 ). Increasing age was associated with greater incidence of serious adverse events with escitalopram (low SOE). The increased risk of falls on duloxetine may be associated with the presence of cardiopulmonary conditions (low SOE). Conclusions. In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs (duloxetine and venlafaxine) led to a greater number of adverse events compared with placebo while adverse events were statistically similar to placebo with SSRIs (escitalopram, fluoxetine), vortioxetine and bupropion. SSRIs (citalopram, escitalopram and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of study withdrawals due to adverse events compared with placebo and duloxetine increased the risk of falls. Further characterization of the comparative safety of antidepressants is difficult because few studies were identified, comparisons were based on statistical significance, trials were not powered to identify small difference in adverse events and observational studies may be confounded. Comparative, long-term, well-designed studies that report specific adverse events are needed to better inform decisionmaking in this population.
Contributor(s): UConn EPC
Funding Source: AHRQ
Methodology Description: MEDLINE®, Embase®, Cochrane Central, and PsycINFO bibliographic databases from earliest date through May 15, 2018; hand searches of references of relevant studies; www.clinicaltrials.gov and the International Controlled Trials Registry Platform. Two investigators screened abstracts and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence (SOE) for each comparison and select outcomes. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings.

Zoom Preview | Show Downloadable Content

Intermittent Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists for Asthma


Public Project Complete

Statistics: 74 Studies, 6 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Objective. To assess efficacy of intermittent inhaled corticosteroid (ICS) therapy in different populations (0 to 4 years old with recurrent wheezing, 5 years and older with persistent asthma, with or without long-acting beta agonist [LABA]), and to assess efficacy of added long-acting muscarinic antagonist (LAMA) in patients 12 years and older with uncontrolled, persistent asthma. Data sources. MEDLINE®, Embase®, Cochrane Central, and Cochrane Database of Systematic Reviews bibliographic databases from earliest date through March 23, 2017; hand searches of references of relevant studies; www.clinicaltrials.gov and the International Controlled Trials Registry Platform. Review methods. Two investigators screened abstracts of identified references for eligibility and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence for each comparison and outcome. Outcomes for which data were extracted included exacerbations, mortality, asthma control composite scores, spirometry, asthma-specific quality of life, and rescue medication use. Results. We included 56 unique studies (54 randomized controlled trials, 2 observational studies) in this review. Compared to rescue short-acting beta-agonist (SABA) use, adding intermittent ICS reduces the risk of exacerbation requiring oral steroids and improves caregiver quality of life in children less than 5 years old with recurrent wheezing in the setting of a respiratory tract infection (RTI). In patients 12 years and older with persistent asthma, differences in intermittent ICS versus controller use of ICS were not detected, although few studies provided evidence, leading to primarily low strength of evidence ratings. Using ICS and LABA as both a controller and quick relief therapy reduced the risk of exacerbations and improved symptom control in patients 12 years and older compared to ICS controller (with or without LABA). Data in patients 4 to 11 years old suggest lower risk of exacerbations with ICS and LABA controller and quick relief use, but with a lower strength of evidence than in the older population. In patients 12 years and older with uncontrolled, persistent asthma, LAMA versus placebo as add-on to ICS reduces the risk of exacerbations requiring systemic corticosteroids and improves lung function measure through spirometry. Current evidence does not suggest that a difference exists in the efficacy of LAMA versus LABA as add-on to ICS. Triple therapy of ICS, LAMA, and LABA improves lung function measured through spirometry, although the risk of exacerbation was not different versus ICS and LABA. Conclusions. Intermittent ICS added to SABA during an RTI provides benefit to patients less than 5 years of age with recurrent wheezing. In patients 12 years and older with persistent asthma, differences in intermittent ICS versus controller use of ICS were not detected, although few studies provided evidence for this question. In patients 12 years and older with persistent asthma, using ICS and LABA as both a controller and quick relief therapy may be more effective at preventing exacerbations than ICS controller (with or without LABA). LAMA is effective in the management of uncontrolled, persistent asthma in patients 12 years of age and older, and current evidence does not suggest a difference between LAMA and LABA as add-on to ICS.
Contributor(s): UConn EPC
Funding Source: AHRQ
Methodology Description: Data sources. MEDLINE®, Embase®, Cochrane Central, and Cochrane Database of Systematic Reviews bibliographic databases from earliest date through March 23, 2017; hand searches of references of relevant studies; www.clinicaltrials.gov and the International Controlled Trials Registry Platform. Review methods. Two investigators screened abstracts of identified references for eligibility and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence for each comparison and outcome. Outcomes for which data were extracted included exacerbations, mortality, asthma control composite scores, spirometry, asthma-specific quality of life, and rescue medication use.

Zoom Preview | Show Downloadable Content

Screening for Elevated Blood Lead Levels in Pregnancy [Entered Retrospectively]


Public Project Complete

Statistics: 2 Studies, 6 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Structured Abstract Background: In 2006, the United States Preventive Services Task Force (USPSTF) recommended against routine screening for elevated blood lead levels in asymptomatic pregnant women (D recommendation). Purpose: To synthesize evidence on the effects of screening, testing, and treatment for elevated blood lead level in pregnant women, in order to update a 2006 USPSTF systematic review. Data Sources: Cochrane CENTRAL and Cochrane Database of Systematic Reviews (through June 2018), and Ovid MEDLINE (1946 to June 2018), reference lists, and surveillance through December 5, 2018. Study Selection: English-language trials and observational studies of screening effectiveness, test accuracy, benefits and harms of screening and interventions in asymptomatic pregnant women. Data Extraction: One investigator abstracted details about study design, patient population, setting, screening method, follow up, and results. Two investigators independently applied prespecified criteria to rate study quality using methods developed by the USPSTF. Discrepancies were resolved through consensus. Data Synthesis: No studies directly evaluated clinical benefits and harms of screening pregnant women for elevated lead levels versus no screening, or how effectiveness of screening varies according to the gestational age at which screening is performed. One fair quality study (N = 314) evaluated the diagnostic accuracy of using a version of the CDC screening questionnaire for lead exposure in children, modified for identifying pregnant women with elevated lead levels. The study used four out of five of the questions from the CDC questionnaire and found a sensitivity of 75.7 percent and specificity of 46.2 percent. The most predictive single item was living in a home built before 1960. One fair quality RCT from Mexico found calcium supplementation in healthy pregnant women (N = 670; mean baseline lead levels ~ 4 µg/dL) associated with a reduction in serum lead levels compared with placebo (difference 11%, p=0.004). No studies reported health outcomes or harms associated with interventions to reduce blood levels in asymptomatic pregnant women. Limitations: Limited to English-language articles; quality and applicability of studies were limited due to flawed study design, poor reporting of statistical outcomes, and loss to follow up. Two studies addressed the key questions, with no evidence on effects of screening or interventions for elevated lead levels in pregnant women on health outcomes. Conclusions: Evidence on the benefits and harms of screening pregnant women for elevated blood lead levels is extremely limited, with no evidence on effects of screening or interventions for lowering elevated blood lead levels in pregnant women on health outcomes.
Contributor(s): Amy G. Cantor, MD, MPH Marian S. McDonagh, PharmD Ian Blazina, MPH Jessica Griffin, MS Sara Grusing, BA Rob Hendrickson, MD
Funding Source: Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No HHSA290201500009I Task Order No. 7)
Methodology Description: Study Selection: English-language trials and observational studies of screening effectiveness, test accuracy, benefits and harms of screening and interventions in asymptomatic pregnant women. Data Extraction: One investigator abstracted details about study design, patient population, setting, screening method, follow up, and results. Two investigators independently applied prespecified criteria to rate study quality using methods developed by the USPSTF. Discrepancies were resolved through consensus.

Zoom Preview | Show Downloadable Content

Comparative Effectiveness of Analgesics to Reduce Acute Pain in the Prehospital Setting


Public Project Complete

Statistics: 67 Studies, 4 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Objective. To assess comparative effectiveness and harms of opioid and nonopioid analgesics administered by emergency medical services for treatment of moderate to severe acute pain in the prehospital setting. Data sources. MEDLINE®, Embase® and Cochrane Central from earliest date through May 9, 2019; hand searches of references of relevant studies and study registries. Review methods. Two investigators screened abstracts, reviewed full-text files, abstracted data and assessed study level risk of bias. We performed meta-analyses when appropriate and graded the strength of evidence (SOE) upon which conclusions were made for a priori determined comparisons and outcomes. We defined the following as clinically important differences: 2 points on a 0 to 10 pain scale, time to analgesia of 5 minutes, 10% absolute risk difference for any adverse event, and 5% absolute risk difference for hypotension, respiratory depression and mental status changes. Results. We included 52 randomized controlled trials and 13 observational studies. Due to the absence or insufficiency of prehospital evidence we based conclusions for initial analgesia on indirect evidence from the emergency department (ED) setting. As initial analgesics, we found no evidence of a clinically important difference in the change of pain scores with opioids versus ketamine administered primarily intravenously (IV) (low SOE), IV acetaminophen (APAP) (low SOE), or nonsteroidal anti-inflammatory drugs (NSAIDs) administered primarily IV (moderate SOE). The combined use of an opioid and ketamine, administered primarily IV, may reduce pain more than an opioid alone at 15 and 30 minutes (low SOE) but we found no evidence of a clinically important difference at 60 minutes (low SOE). We found no evidence of a clinically important difference in time-to-analgesia with opioids compared with APAP, both administered IV. Opioids may cause fewer adverse events than ketamine (low SOE), primarily administered intranasally (IN). Opioids cause less dizziness than ketamine (low SOE) but may increase the risk of respiratory depression compared with ketamine (low SOE), primarily administered IV. Opioids cause more dizziness (moderate SOE) and may cause more adverse events than APAP (low SOE), both administered IV, but we found no evidence of a clinically important difference in hypotension (low SOE). Opioids may cause more adverse events and more drowsiness than NSAIDs (low SOE), administered primarily IV. Evidence on comparative effects of nitrous oxide and on harms of combined opioid and ketamine is insufficient. For patients whose pain is not adequately reduced by IV morphine initially, we found that giving IV ketamine may reduce pain more and may be quicker than giving additional IV morphine (low SOE, insufficient evidence to determine comparative harms). Conclusion. As initial analgesia administered primarily IV, opioids are no different than ketamine, APAP and NSAIDs in reducing acute pain in the prehospital setting. Opioids may cause fewer total side effects than ketamine, but more than APAP or NSAIDs. Differences in specific side effects vary between analgesics and can further inform treatment decisions. Combined administration of an opioid and ketamine may reduce acute pain more than an opioid alone but comparative harms are uncertain. When initial morphine is inadequate in reducing pain, giving ketamine may provide greater and quicker acute pain relief than giving additional morphine, although comparative harms are uncertain. Due to indirectness, strength of evidence is generally low, and future research in the prehospital setting is needed.
Contributor(s): UConn EPC
Funding Source: AHRQ
Methodology Description: None Provided

Zoom Preview | Show Downloadable Content

Pre-Exposure Prophylaxis for the Prevention of HIV Infection [Entered Retrospectively]


Public Project Complete

Statistics: 52 Studies, 5 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Background: Effective prevention strategies for HIV infection are an important public health priority. Pre-exposure prophylaxis (PrEP) involves use of antiretroviral therapy (ART) regularly (e.g., daily) or before and after HIV exposure events to decrease the risk of acquiring HIV infection. Purpose: To synthesize evidence for the U.S. Preventive Services Task Force (USPSTF) on effects of PrEP on risk of HIV acquisition, mortality, harms, and other clinical outcomes; effects of adherence on PrEP-associated outcomes; and accuracy of methods for identifying potential candidates for PrEP. Data Sources: We searched the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, MEDLINE, and Embase from inception to June 2018 and manually reviewed reference lists; additional surveillance for new literature was conducted through January 25, 2019. Study Selection: Randomized, controlled trials on the benefits and harms of PrEP versus placebo or no PrEP in adults without HIV infection at high risk of becoming infected; studies on the diagnostic accuracy of instruments for predicting incident HIV infection; studies on effects of adherence to PrEP on risk of HIV infection; and studies on rates of adherence to PrEP in U.S. populations. Data Extraction: One investigator abstracted data and a second investigator checked data abstraction for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF. Data Synthesis (Results): In populations at higher risk of acquiring HIV infection, PrEP was associated with decreased risk of HIV infection versus placebo or no PrEP (11 trials; relative risk [RR], 0.46 [95% confidence interval (CI), 0.33 to 0.66; I2=67%; absolute risk reduction, -2.0% [95% CI, -2.8% to -1.2%] after 4 months to 4 years). Effects were consistent across HIV risk categories and for PrEP with tenofovir disoproxil fumarate plus emtricitabine or tenofovir alone. There was a strong association between higher adherence and greater efficacy (adherence ≥70%: 6 trials; RR, 0.27 [95% CI, 0.19 to 0.39]; I2=0%; adherence >40% to <70%: 3 trials; RR, 0.51 [95% CI, 0.38 to 0.70]; I2=0%; and adherence ≤40%: 2 trials; RR, 0.93 [95% CI, 0.72 to 1.20]; I2=0%; p<0.00001 for interaction). No trial reported effects of nondaily dosing except for one trial of event-driven PrEP (RR, 0.14 [95% CI, 0.03 to 0.63]). There was no difference between PrEP and placebo or no PrEP in risk of serious adverse events (12 trials; RR, 0.93 [95% CI, 0.77 to 1.12]; I2=56%). PrEP was associated with increased risk of renal adverse events (12 trials; RR, 1.43 [95% CI, 1.18 to 1.75]; I2=0%; absolute risk difference, 0.56% [95% CI, 0.09% to 1.04%]) and gastrointestinal adverse events (12 trials; RR, 1.63 [95% CI, 1.26 to 2.11]; I2=43%; absolute risk difference, 1.95% [95% CI, 0.48% to 3.43%]); most adverse events were mild and resolved with discontinuation of PrEP or with longer therapy. The association between PrEP and fracture was not statistically significant (7 trials; RR, 1.23 [95% CI, 0.97 to 1.56]; I2=0%). There were no differences between PrEP and placebo in risk of sexually transmitted infections, but most trials were blinded. Among women who became pregnant in trials of PrEP, PrEP was not associated with increased risk of spontaneous abortion (3 trials; RR, 1.09 [95% CI, 0.79 to 1.50]; I2=0%) or other adverse pregnancy outcomes. Instruments for predicting risk of incident HIV infection had moderate discrimination and require further validation. Adherence to PrEP in U.S. populations of men who have sex with men varied from high to low. Limitations: Restricted to English language, statistical heterogeneity in some pooled analyses, most randomized trials were conducted in low-income settings, limited evidence on adherence in U.S. populations, and evidence lacking in adolescents and pregnant women. Conclusions: In adults at increased risk of HIV infection, oral PrEP with tenofovir or tenofovir disoproxil fumarate plus emtricitabine is associated with decreased risk of HIV infection compared with placebo or no PrEP, although effectiveness decreases with inadequate adherence. PrEP is associated with increased risk of renal and gastrointestinal adverse events. Evidence on the accuracy of instruments for identifying persons at high risk of HIV infection is limited, with further validation needed.
Contributor(s): Roger Chou, MD Christopher Evans, MD, MPH Adam Hoverman, DO, DTM&H Christina Sun, PhD Tracy Dana, MLS Christina Bougatsos, MPH Sara Grusing, BS P. Todd Korthuis, MD, MPH
Funding Source: This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2015-00009-I, Task Order No. 10)
Methodology Description: Study Selection: Randomized, controlled trials on the benefits and harms of PrEP versus placebo or no PrEP in adults without HIV infection at high risk of becoming infected; studies on the diagnostic accuracy of instruments for predicting incident HIV infection; studies on effects of adherence to PrEP on risk of HIV infection; and studies on rates of adherence to PrEP in U.S. populations. Data Extraction: One investigator abstracted data and a second investigator checked data abstraction for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF.

Zoom Preview | Show Downloadable Content