A systematic review and meta-analysis of efficacy, cost-effectiveness, and safety of selected complementary and alternative medicine for neck and low-back pain.

Background. Back pain is a common problem and a major cause of disability and health care utilization. Purpose. To evaluate the efficacy, harms, and costs of the most common CAM treatments (acupuncture, massage, spinal manipulation, and mobilization) for neck/low-back pain. Data Sources. Records without language restriction from various databases up to February 2010. Data Extraction. The efficacy outcomes of interest were pain intensity and disability. Data Synthesis. Reports of 147 randomized trials and 5 nonrandomized studies were included. CAM treatments were more effective in reducing pain and disability compared to no treatment, physical therapy (exercise and/or electrotherapy) or usual care immediately or at short-term follow-up. Trials that applied sham-acupuncture tended towards statistically nonsignificant results. In several studies, acupuncture caused bleeding on the site of application, and manipulation and massage caused pain episodes of mild and transient nature. Conclusions. CAM treatments were significantly more efficacious than no treatment, placebo, physical therapy, or usual care in reducing pain immediately or at short-term after treatment. CAM therapies did not significantly reduce disability compared to sham. None of the CAM treatments was shown systematically as superior to one another. More efforts are needed to improve the conduct and reporting of studies of CAM treatments.

Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis.

OBJECTIVE: To examine the safety, effectiveness, and cost effectiveness of long acting insulin for type 1 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, and grey literature were searched through January 2013. STUDY SELECTION: Randomized controlled trials or non-randomized studies of long acting (glargine, detemir) and intermediate acting (neutral protamine Hagedorn (NPH), lente) insulin for adults with type 1 diabetes were included. RESULTS: 39 studies (27 randomized controlled trials including 7496 patients) were included after screening of 6501 titles/abstracts and 190 full text articles. Glargine once daily, detemir once daily, and detemir once/twice daily significantly reduced hemoglobin A1c compared with NPH once daily in network meta-analysis (26 randomized controlled trials, mean difference -0.39%, 95% confidence interval -0.59% to -0.19%; -0.26%, -0.48% to -0.03%; and -0.36%, -0.65% to -0.08%; respectively). Differences in network meta-analysis were observed between long acting and intermediate acting insulin for severe hypoglycemia (16 randomized controlled trials; detemir once/twice daily versus NPH once/twice daily: odds ratio 0.62, 95% confidence interval 0.42 to 0.91) and weight gain (13 randomized controlled trials; detemir once daily versus NPH once/twice daily: mean difference 4.04 kg, 3.06 to 5.02 kg; detemir once/twice daily versus NPH once daily: -5.51 kg, -6.56 to -4.46 kg; glargine once daily versus NPH once daily: -5.14 kg, -6.07 to -4.21). Compared with NPH, detemir was less costly and more effective in 3/14 cost effectiveness analyses and glargine was less costly and more effective in 2/8 cost effectiveness analyses. The remaining cost effectiveness analyses found that detemir and glargine were more costly but more effective than NPH. Glargine was not cost effective compared with detemir in 2/2 cost effectiveness analyses. CONCLUSIONS: Long acting insulin analogs are probably superior to intermediate acting insulin analogs, although the difference is small for hemoglobin A1c. Patients and their physicians should tailor their choice of insulin according to preference, cost, and accessibility. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013003610.

A surveillance system to assess the need for updating systematic reviews.

BACKGROUND: Systematic reviews (SRs) can become outdated as new evidence emerges over time. Organizations that produce SRs need a surveillance method to determine when reviews are likely to require updating. This report describes the development and initial results of a surveillance system to assess SRs produced by the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program. METHODS: Twenty-four SRs were assessed using existing methods that incorporate limited literature searches, expert opinion, and quantitative methods for the presence of signals triggering the need for updating. The system was designed to begin surveillance six months after the release of the original review, and then ceforth every six months for any review not classified as being a high priority for updating. The outcome of each round of surveillance was a classification of the SR as being low, medium or high priority for updating. RESULTS: Twenty-four SRs underwent surveillance at least once, and ten underwent surveillance a second time during the 18 months of the program. Two SRs were classified as high, five as medium, and 17 as low priority for updating. The time lapse between the searches conducted for the original reports and the updated searches (search time lapse - STL) ranged from 11 months to 62 months: The STL for the high priority reports were 29 months and 54 months; those for medium priority reports ranged from 19 to 62 months; and those for low priority reports ranged from 11 to 33 months. Neither the STL nor the number of new relevant articles was perfectly associated with a signal for updating. Challenges of implementing the surveillance system included determining what constituted the actual conclusions of an SR that required assessing; and sometimes poor response rates of experts. CONCLUSION: In this system of regular surveillance of 24 systematic reviews on a variety of clinical interventions produced by a leading organization, about 70% of reviews were determined to have a low priority for updating. Evidence suggests that the time period for surveillance is yearly rather than the six months used in this project.

Diagnosis and management of febrile infants (0-3 months).

OBJECTIVES: To review the evidence for diagnostic accuracy of screening for serious bacterial illness (SBI) and invasive herpes simplex virus (HSV) infection in febrile infants 3 months or younger; ascertain harms and benefits of various management strategies; compare prevalence of SBI and HSV between different clinical settings; determine how well the presence of viral infection predicts against SBI; and review evidence on parental compliance to return for followup assessments (infants less than 6 months). DATA SOURCES: MEDLINE, CINAHL, Embase, Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, abstracts, and unpublished materials. REVIEW METHODS: Two independent reviewers screened the literature and extracted data on population characteristics, index/diagnostic test characteristics. Diagnostic test accuracy studies were assessed using Quality Assessment of Diagnostic Accuracy Studies. RESULTS: Eighty-four original studies were included. The combined clinical and laboratory criteria (Rochester, Philadelphia, Boston, and Milwaukee) demonstrated similar overall accuracy (sensitivity: 84.4 percent to 100.0 percent; specificity: 26.6 percent to 69.0 percent; negative predictive value: 93.7 percent to 100.0 percent; and positive predictive value: 3.3 percent to 48.6 percent) for identifying infants with SBI. The criteria based on history of recent immunization or rapid influenza test demonstrated higher sensitivity but lower specificity compared with criteria based on age, gender, and the degree of fever. The overall accuracy of C-reactive protein was greater than that for absolute neutrophil count and absolute band counts , white blood cell, and procalcitonin. For correctly identifying infants with and without SBI (or bacteremia), the Boston, Philadelphia, and Milwaukee criteria/protocol showed better overall accuracy when applied to older infants versus neonates. The Rochester criteria were more accurate in neonates than in older infants. Evidence on HSV was scarce. Most of the criteria/protocols demonstrated high negative predictive values and low positive predictive values for correctly predicting the absence or presence of SBI. In studies reporting outcomes of delayed treatment for infants with SBI initially classified as low risk, all infants recovered uneventfully. The reported adverse events following immediate antibiotic therapy were limited to drug related rash and infiltration of intravenous line. There was a higher prevalence of SBI in infants without viral infection or clinical bronchiolitis compared to infants with viral infection or bronchiolitis. The prevalence of SBI tended to be higher in the emergency departments versus primary care setting offices. The parental compliance to followup for return visits/reassessment of infants after initial examination across four studies ranged from 77.4 percent to 99.8 percent. There was no evidence to determine the influence of parental factors and clinical settings on the degree of parental compliance. CONCLUSIONS: Overall, the focus of the literature has been on ruling out SBI. Harms associated with testing or management strategies have been less well studied. Combined criteria showed fairly high sensitivity and (therefore) reliability in not missing possible cases of SBI. Attempts to identify high-risk groups specifically, described in a minority of reports, were not as successful. There is very little literature on factors associated with compliance to followup care, although that information could be crucial to improving management strategies in the low-risk group. Future studies should focus on identifying the risks associated with testing and management strategies and factors that predict compliance.

Pre-analytic and analytic sources of variations in thiopurine methyltransferase activity measurement in patients prescribed thiopurine-based drugs: A systematic review.

OBJECTIVES: Low thiopurine S-methyltransferase (TPMT) enzyme activity is associated with increased thiopurine drug toxicity, particularly myelotoxicity. Pre-analytic and analytic variables for TPMT genotype and phenotype (enzyme activity) testing were reviewed. DESIGN AND METHODS: A systematic literature review was performed, and diagnostic laboratories were surveyed. RESULTS: Thirty-five studies reported relevant data for pre-analytic variables (patient age, gender, race, hematocrit, co-morbidity, co-administered drugs and specimen stability) and thirty-three for analytic variables (accuracy, reproducibility). TPMT is stable in blood when stored for up to 7 days at room temperature, and 3 months at -30°C. Pre-analytic patient variables do not affect TPMT activity. Fifteen drugs studied to date exerted no clinically significant effects in vivo. Enzymatic assay is the preferred technique. Radiochemical and HPLC techniques had intra- and inter-assay coefficients of variation (CVs) below 10%. CONCLUSION: TPMT is a stable enzyme, and its assay is not affected by age, gender, race or co-morbidity.

Development quality criteria to evaluate nontherapeutic studies of incidence, prevalence, or risk factors of chronic diseases: pilot study of new checklists.

OBJECTIVE: To develop two checklists for the quality of observational studies of incidence or risk factors of diseases. STUDY DESIGN AND SETTING: Initial development of the checklists was based on a systematic literature review. The checklists were refined after pilot trials of validity and reliability were conducted by seven experts, who tested the checklists on 10 articles. RESULTS: The checklist for studies of incidence or prevalence of chronic disease had six criteria for external validity and five for internal validity. The checklist for risk factor studies had six criteria for external validity, 13 criteria for internal validity, and two aspects of causality. A Microsoft Access database produced automated standardized reports about external and internal validities. Pilot testing demonstrated face and content validities and discrimination of reporting vs. methodological qualities. Interrater agreement was poor. The experts suggested future reliability testing of the checklists in systematic reviews with preplanned protocols, a priori consensus about research-specific quality criteria, and training of the reviewers. CONCLUSION: We propose transparent and standardized quality assessment criteria of observational studies using the developed checklists. Future testing of the checklists in systematic reviews is necessary to develop reliable tools that can be used with confidence.

Complementary and alternative therapies for back pain II.

BACKGROUND: Back and neck pain are important health problems with serious societal and economic implications. Conventional treatments have been shown to have limited benefit in improving patient outcomes. Complementary and Alternative Medicine (CAM) therapies offer additional options in the management of low back and neck pain. Many trials evaluating CAM therapies have poor quality and inconsistent results. OBJECTIVES: To systematically review the efficacy, effectiveness, cost-effectiveness, and harms of acupuncture, spinal manipulation, mobilization, and massage techniques in management of back, neck, and/or thoracic pain. DATA SOURCES: MEDLINE, Cochrane Central, Cochrane Database of Systematic Reviews, CINAHL, and EMBASE were searched up to 2010; unpublished literature and reference lists of relevant articles were also searched. study selection: All records were screened by two independent reviewers. Primary reports of comparative efficacy, effectiveness, harms, and/or economic evaluations from randomized controlled trials (RCTs) of the CAM therapies in adults (age ≥ 18 years) with back, neck, or thoracic pain were eligible. Non-randomized controlled trials and observational studies (case-control, cohort, cross-sectional) comparing harms were also included. Reviews, case reports, editorials, commentaries or letters were excluded. DATA EXTRACTION: Two independent reviewers using a predefined form extracted data on study, participants, treatments, and outcome characteristics. RESULTS: 265 RCTs and 5 non-RCTs were included. Acupuncture for chronic nonspecific low back pain was associated with significantly lower pain intensity than placebo but only immediately post-treatment (VAS: -0.59, 95 percent CI: -0.93, -0.25). However, acupuncture was not different from placebo in post-treatment disability, pain medication intake, or global improvement in chronic nonspecific low back pain. Acupuncture did not differ from sham-acupuncture in reducing chronic non-specific neck pain immediately after treatment (VAS: 0.24, 95 percent CI: -1.20, 0.73). Acupuncture was superior to no treatment in improving pain intensity (VAS: -1.19, 95 percent CI: 95 percent CI: -2.17, -0.21), disability (PDI), functioning (HFAQ), well-being (SF-36), and range of mobility (extension, flexion), immediately after the treatment. In general, trials that applied sham-acupuncture tended to produce negative results (i.e., statistically non-significant) compared to trials that applied other types of placebo (e.g., TENS, medication, laser). Results regarding comparisons with other active treatments (pain medication, mobilization, laser therapy) were less consistent Acupuncture was more cost-effective compared to usual care or no treatment for patients with chronic back pain. For both low back and neck pain, manipulation was significantly better than placebo or no treatment in reducing pain immediately or short-term after the end of treatment. Manipulation was also better than acupuncture in improving pain and function in chronic nonspecific low back pain. Results from studies comparing manipulation to massage, medication, or physiotherapy were inconsistent, either in favor of manipulation or indicating no significant difference between the two treatments. Findings of studies regarding costs of manipulation relative to other therapies were inconsistent. Mobilization was superior to no treatment but not different from placebo in reducing low back pain or spinal flexibility after the treatment. Mobilization was better than physiotherapy in reducing low back pain (VAS: -0.50, 95 percent CI: -0.70, -0.30) and disability (Oswestry: -4.93, 95 percent CI: -5.91, -3.96). In subjects with acute or subacute neck pain, mobilization compared to placebo significantly reduced neck pain. Mobilization and placebo did not differ in subjects with chronic neck pain. Massage was superior to placebo or no treatment in reducing pain and disability only amongst subjects with acute/sub-acute low back pain. Massage was also significantly better than physical therapy in improving back pain (VAS: -2.11, 95 percent CI: -3.15, -1.07) or disability. For subjects with neck pain, massage was better than no treatment, placebo, or exercise in improving pain or disability, but not neck flexibility. Some evidence indicated higher costs for massage use compared to general practitioner care for low back pain. Reporting of harms in RCTs was poor and inconsistent. Subjects receiving CAM therapies reported soreness or bleeding on the site of application after acupuncture and worsening of pain after manipulation or massage. In two case-control studies cervical manipulation was shown to be significantly associated with vertebral artery dissection or vertebrobasilar vascular accident. CONCLUSIONS: Evidence was of poor to moderate grade and most of it pertained to chronic nonspecific pain, making it difficult to draw more definitive conclusions regarding benefits and harms of CAM therapies in subjects with acute/subacute, mixed, or unknown duration of pain. The benefit of CAM treatments was mostly evident immediately or shortly after the end of the treatment and then faded with time. Very few studies reported long-term outcomes. There was insufficient data to explore subgroup effects. The trial results were inconsistent due probably to methodological and clinical diversity, thereby limiting the extent of quantitative synthesis and complicating interpretation of trial results. Strong efforts are warranted to improve the conduct methodology and reporting quality of primary studies of CAM therapies. Future well powered head to head comparisons of CAM treatments and trials comparing CAM to widely used active treatments that report on all clinically relevant outcomes are needed to draw better conclusions.

Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs.

OBJECTIVES: To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. DATA SOURCES: MEDLINE®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, Genetics Abstracts, and EconLit™ to May 2009, for English language records. REVIEW METHODS: A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. RESULTS: 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. CONCLUSIONS: There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.