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Background: Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection., Purpose: To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection., Data Sources: MEDLINE and EMBASE from inception through 1 November 2016., Study Selection: 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs., Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently., Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without., Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling., Conclusion: Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis., Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711).

Background: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices., Purpose: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes., Data Sources: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015)., Study Selection: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations., Data Extraction: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence., Data Synthesis: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors., Limitation: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes., Conclusion: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: N-acetylcysteine, sodium bicarbonate, statins, and ascorbic acid have been studied for reducing contrast-induced nephropathy (CIN)., Purpose: To evaluate the comparative effectiveness of interventions to reduce CIN in adults receiving contrast media., Data Sources: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and Scopus databases through June 2015. Risk of bias and overall strength of evidence (SOE) of studies were assessed., Study Selection: Randomized, controlled trials of N-acetylcysteine, sodium bicarbonate, statins, or ascorbic acid that used intravenous (IV) or intra-arterial contrast media and defined CIN with enough data for meta-analysis., Data Extraction: Two reviewers independently extracted data and assessed study quality., Data Synthesis: Low-dose N-acetylcysteine plus IV saline compared with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to 0.89]; low SOE), N-acetylcysteine plus IV saline compared with IV saline in patients receiving low-osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84]; moderate SOE), and statins plus N-acetylcysteine plus IV saline versus N-acetylcysteine plus IV saline (RR, 0.52 [CI, 0.29 to 0.93]; low SOE) had clinically important and statistically significant benefits. The following 3 comparisons suggested a clinically important difference that was not statistically significant: sodium bicarbonate versus IV saline in patients receiving low-osmolar contrast media (RR, 0.65 [CI, 0.33 to 1.25]; low SOE), statins plus IV saline versus IV saline (RR, 0.68 [CI, 0.39 to 1.20]; low SOE), and ascorbic acid versus IV saline (RR, 0.72 [CI, 0.48 to 1.01]; low SOE). Strength of evidence was generally insufficient for comparisons of the need for renal replacement, cardiac events, and mortality., Limitation: Too few studies were done in patients receiving IV contrast media., Conclusion: The greatest reduction in CIN was seen with N-acetylcysteine plus IV saline in patients receiving LOCM and with statins plus N-acetylcysteine plus IV saline., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Iodine contrast media are essential components of many imaging procedures. An important potential side effect is contrast-induced nephropathy (CIN)., Purpose: To compare CIN risk for contrast media within and between osmolality classes in patients receiving diagnostic or therapeutic imaging procedures., Data Sources: PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and Scopus through June 2015., Study Selection: Randomized, controlled trials that reported CIN-related outcomes in patients receiving low-osmolar contrast media (LOCM) or iso-osmolar contrast media for imaging., Data Extraction: Independent study selection and quality assessment by 2 reviewers and dual extraction of study characteristics and results., Data Synthesis: None of the 5 studies that compared types of LOCM reported a statistically significant or clinically important difference among study groups, but the strength of evidence was low. Twenty-five randomized, controlled trials found a slight reduction in CIN risk with the iso-osmolar contrast media agent iodixanol compared with a diverse group of LOCM that just reached statistical significance in a meta-analysis (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P = 0.045). This comparison's strength of evidence was moderate. In a meta regression of randomized, controlled trials of iodixanol, no relationship was found between route of administration and comparative CIN risk., Limitations: Few studies compared LOCM. Procedural details about contrast administration were not uniformly reported. Few studies specified clinical indications or severity of baseline renal impairment., Conclusion: No differences were found in CIN risk among types of LOCM. Iodixanol had a slightly lower risk for CIN than LOCM, but the lower risk did not exceed a criterion for clinical importance., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Patients with chronic kidney disease (CKD) have high prevalence of elevated serum troponin levels, which makes diagnosis of acute coronary syndrome (ACS) challenging., Purpose: To evaluate the utility of troponin in ACS diagnosis, treatment, and prognosis among patients with CKD., Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014., Study Selection: Studies examining elevated versus normal troponin levels in terms of their diagnostic performance in detection of ACS, effect on ACS management strategies, and prognostic value for mortality or cardiovascular events after ACS among patients with CKD., Data Extraction: Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE)., Data Synthesis: Twenty-three studies met inclusion criteria. The sensitivity of troponin T for ACS diagnosis ranged from 71% to 100%, and specificity ranged from 31% to 86% (6 studies; low SOE). The sensitivity and specificity of troponin I ranged from 43% to 94% and from 48% to 100%, respectively (8 studies; low SOE). No studies examined how troponin levels affect management strategies. Twelve studies analyzed prognostic value. Elevated levels of troponin I or troponin T were associated with higher risk for short-term death and cardiac events (low SOE). A similar trend was observed for long-term mortality with troponin I (low SOE), but less evidence was found for long-term cardiac events for troponin I and long-term outcomes for troponin T (insufficient SOE). Patients with advanced CKD tended to have worse prognoses with elevated troponin I levels than those without them (moderate SOE)., Limitation: Studies were heterogeneous in design and in ACS definitions and adjudication methods., Conclusion: In patients with CKD and suspected ACS, troponin levels can aid in identifying those with a poor prognosis, but the diagnostic utility is limited by varying estimates of sensitivity and specificity., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Clinicians face uncertainty about the prognostic value of troponin testing in patients with chronic kidney disease (CKD) without suspected acute coronary syndrome (ACS)., Purpose: To systematically review the literature on troponin testing in patients with CKD without ACS., Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014., Study Selection: Studies examining elevated versus normal troponin levels in patients with CKD without ACS., Data Extraction: Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE). Meta-analyses were conducted when studies had sufficient homogeneity of key variables., Data Synthesis: Ninety-eight studies met inclusion criteria. Elevated troponin levels were associated with all-cause and cardiovascular mortality among patients receiving dialysis (moderate SOE). Pooled hazard ratios (HRs) for all-cause mortality from studies that adjusted for age and coronary artery disease or a risk equivalent were 3.0 (95% CI, 2.4 to 4.3) for troponin T and 2.7 (CI, 1.9 to 4.6) for troponin I. The pooled adjusted HRs for cardiovascular mortality were 3.3 (CI, 1.8 to 5.4) for troponin T and 4.2 (CI, 2.0 to 9.2) for troponin I. Findings were similar for patients with CKD who were not receiving dialysis, but there were fewer studies. No study tested treatment strategies by troponin cut points., Limitation: Studies were heterogeneous regarding assays, troponin cut points, covariate adjustment, and follow-up., Conclusion: In patients with CKD without suspected ACS, elevated troponin levels were associated with worse prognosis. Future studies should focus on whether this biomarker is more appropriate than clinical models for reclassifying risk of patients with CKD and whether such classification can help guide treatment in those at highest risk for death., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Glaucoma is an acquired degeneration of the optic nerve and a leading cause of blindness worldwide. Medical and surgical treatments that decrease intraocular pressure may prevent visual impairment and blindness., Purpose: To compare the effectiveness of medical, laser, and surgical treatments in adults with open-angle glaucoma with regard to decreasing intraocular pressure and preventing optic nerve damage, vision loss, and visual impairment., Data Sources: MEDLINE, CENTRAL, and an existing database for systematic reviews (through 2 March 2011); MEDLINE, EMBASE, LILACS, and CENTRAL for primary studies (through 30 July 2012)., Study Selection: English-language systematic reviews; randomized, controlled trials; and quasi-randomized, controlled trials for most outcomes and observational studies for quality of life and harms., Data Extraction: Two investigators abstracted or checked information about study design, participants, and outcomes and assessed risk of bias and strength of evidence., Data Synthesis: High-level evidence suggests that medical, laser, and surgical treatments decrease intraocular pressure and that medical treatment and trabeculectomy reduce the risk for optic nerve damage and visual field loss compared with no treatment. The direct effect of treatments on visual impairment and the comparative efficacy of different treatments are not clear. Harms of medical treatment are primarily local (ocular redness, irritation); surgical treatment carries a small risk for more serious complications., Limitation: Heterogeneous outcome definitions and measurements among the included studies; exclusion of many treatment studies that did not stratify results by glaucoma type., Conclusion: Medical and surgical treatments for open-angle glaucoma lower intraocular pressure and reduce the risk for optic nerve damage over the short to medium term. Which treatments best prevent visual disability and improve patient-reported outcomes is unclear.