Systematic review and meta-analysis of endovascular and surgical revascularization for patients with chronic lower extremity venous insufficiency and varicose veins.

BACKGROUND: Chronic lower extremity venous disease (LECVD) is twice as prevalent as coronary heart disease, and invasive therapies to treat LECVD accounted for an estimated $290 million in Medicare expenditures in 2015. Despite increasing use of these invasive therapies, their comparative effectiveness is unknown. METHODS: We conducted a systematic review and meta-analysis of treatments for patients (symptomatic and asymptomatic) with lower extremity varicosities and/or lower extremity chronic venous insufficiency/incompetence/reflux. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for relevant English-language studies published from January 2000 to July 2016. We included comparative randomized controlled trials (RCTs) with >20 patients and observational studies with >500 patients. Short-, intermediate-, and long-term outcomes of placebo, mechanical compression therapy, and invasive therapies (surgical and endovascular) were included. Quality ratings and evidence grading was performed. Random-effects models were used to compute summary estimates of effects. RESULTS: We identified a total of 57 studies representing 105,878 enrolled patients, including 53 RCTs comprised of 10,034 patients. Among the RCTs, 16 were good quality, 28 were fair quality, and 9 were poor quality. Allocation concealment, double blinding, and reporting bias were inadequately addressed in 25 of 53 (47%), 46 of 53 (87%), and 15 of 53 (28.3%), respectively. Heterogeneity in therapies, populations, and/or outcomes prohibited meta-analysis of comparisons between different endovascular therapies and between endovascular intervention and placebo/compression. Meta-analysis evaluating venous stripping plus ligation (high ligation/stripping) compared with radiofrequency ablation revealed no difference in short-term bleeding (odds ratio [OR]=0.30, 95% CI -0.16 to 5.38, P=.43) or reflux recurrence at 1-2 years (OR=0.76, 95% CI 0.37-1.55, P=.44). Meta-analysis evaluating high ligation/stripping versus endovascular laser ablation revealed no difference in long-term symptom score (OR 0.02, 95% CI -0.19 to 0.23, P=.84) or quality of life at 2 years (OR 0.06, 95% CI -0.12 to 0.25, P=.50). CONCLUSIONS: The paucity of high-quality comparative effectiveness and safety data in LECVD is concerning given the overall rise in endovascular procedures. More high-quality studies are needed to determine comparative effectiveness and guide policy and practice.

The Systemic Juvenile Idiopathic Arthritis Cohort of the Childhood Arthritis and Rheumatology Research Alliance Registry: 2010-2013.

OBJECTIVE: We aimed to identify the (1) demographic/clinical characteristics, (2) medication usage trends, (3) variables associated with worse disease activity, and (4) characteristics of patients with persistent chronic arthritis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry's systemic juvenile idiopathic arthritis (sJIA) cohort. METHODS: Demographics, disease activity measures, and medications at enrollment of patients with sJIA in the CARRA Registry were analyzed using descriptive statistics. Multivariate analyses were conducted to identify associations with increased disease activity. Medication usage frequencies were calculated by year. RESULTS: There were 528 patients with sJIA enrolled in the registry (2010-2013). There were 435 patients who had a complete dataset; of these, 372 met the International League of Associations for Rheumatology criteria and were included in the analysis. At enrollment, median disease duration and joint count were 3.7 years and 0, respectively; 16.4% had a rash and 6.7% had a fever. Twenty-six percent were taking interleukin 1 (IL-1) inhibitors and 29% glucocorticoids. Disease-modifying antirheumatic drugs and tumor necrosis factor inhibitors use decreased, while IL-6 inhibitor use increased between 2010 and 2013. African American patients had worse joint counts (p = 0.003), functional status (p = 0.01), and physician's global assessment (p = 0.008). Of the 255 subjects with > 2 years of disease duration, 56% had no arthritis or systemic symptoms, while 32% had persistent arthritis only. CONCLUSION: Most patients in the largest sJIA cohort reported to date had low disease activity. Practice patterns for choice of biologic agents appeared to change over the study period. Nearly one-third had persistent arthritis without systemic symptoms > 2 years after onset. African Americans were associated with worse disease activity. Strategies are needed to improve outcomes in subgroups with poor prognosis.

Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review.

BACKGROUND: Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non-ST-segment-elevation myocardial infarction patients. METHODS AND RESULTS: We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. CONCLUSIONS: Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non-ST-segment-elevation myocardial infarction treated with DAPT are warranted.

Dual antiplatelet therapy with or without oral anticoagulation in the postdischarge management of acute coronary syndrome patients with an indication for long term anticoagulation: a systematic review.

Currently, there is a lack of consensus among guidelines for the postdischarge treatment of patients presenting with acute coronary syndrome (ACS) who have a long-term indication for anticoagulation. We conducted a systematic review comparing the safety and effectiveness of dual antiplatelet therapy (DAPT) and triple therapy (TT; defined as DAPT plus an oral anticoagulant) in patients with ACS and a long-term indication for anticoagulation. We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews published between January 1995 and September 2013. Each investigator screened and abstracted data, assessed applicability and quality, and graded the strength of evidence. Meta-analysis of direct comparison was performed when outcomes and follow-up periods were comparable. Fourteen observational studies were identified that contained comparative effectiveness data on DAPT versus TT. No difference in the odds of mortality (OR 1.04, 95% CI 0.59-1.83) or stroke (OR 1.01, 95% CI 0.38-2.67) at 1-5 years was found between TT and DAPT. Major bleeding at 1-5 years (OR 1.46, 95% CI 1.07-2.00) and nonfatal MI at 1-5 years (OR 1.85, 95% CI 1.13-3.02) occurred more frequently in patients receiving TT. The results of this systematic review demonstrate that treatment with TT was associated with increased rates of nonfatal MI and major bleeding when compared with treatment with DAPT in the postdischarge management of ACS patients with an indication for oral anticoagulation. Until results of ongoing randomized trials assessing antithrombotic therapies define optimal management strategies, the current analysis suggests using caution when prescribing TT to these patients.

Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis.

BACKGROUND: Understanding the comparative effectiveness of treatments for patients with unexplained or refractory cough is important to increase awareness of proven therapies and their potential adverse effects in this unique population. METHODS: We performed a literature search for English-language studies published up to June 2012 that compared symptomatic therapies for chronic cough. Two investigators screened each abstract and full-text article for inclusion, abstracted data, and rated quality. Meta-analysis with random-effects models was used to summarize effects of treatments. RESULTS: We identified 49 studies (3,067 patients) comprising 68 therapeutic comparisons. Of the studied agents, opioid and certain nonopioid and nonanesthetic antitussives had demonstrated efficacy for chronic cough in adults. Compared with placebo, effect sizes (standardized mean differences for cough severity and rate ratios for cough frequency) for opioids were 0.55 (95% CI, 0.38-0.72; P < .0001) and 0.57 (95% CI, 0.36-0.91; P = .0260), respectively. For dextromethorphan, effect sizes were 0.37 (95% CI, 0.19-0.56; P = .0008) and 0.40 (95% CI, 0.18-0.85; P = .0248), respectively. The overall strength of evidence was limited by inconsistency and imprecision of results and by small numbers of direct comparisons. Nonpharmacologic therapies and the management of cough in children were infrequently studied. CONCLUSIONS: Although evidence is limited, opioid and certain nonopioid and nonanesthetic antitussives demonstrated efficacy for treating chronic cough in adults. There is a need for further studies in patients with unexplained or refractory cough as well as for more systematic study designs, assessment of patient-centered outcomes, and reporting.

Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy.

BACKGROUND: Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes. METHODS: Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days. RESULTS: In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials. CONCLUSIONS: Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.

Making Sense of Qualitative and Quantitative Findings in Mixed Research Synthesis Studies.

The synthesis of qualitative and quantitative research findings is increasingly promoted, but many of the conceptual and methodological issues it raises have yet to be fully understood and resolved. In this article, we describe how we handled issues encountered in efforts to synthesize the findings in forty-two reports of studies of antiretroviral adherence in HIV-positive women in the course of an ongoing study to develop methods to synthesize qualitative and quantitative research findings in common domains of health-related research. Working with these reports underscored the importance of looking past method claims and ideals and directly at the findings themselves, differentiating between aggregative syntheses in which findings are assimilated and interpretive syntheses in which they are configured, and understanding the judgments involved in designating relationships between findings as confirmatory, divergent, or complementary.

Physical examination tests for assessing a torn meniscus in the knee: a systematic review with meta-analysis.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVES: To identify, analyze, and synthesize the literature to determine which physical examination tests, if any, accurately diagnose a torn tibial meniscus. BACKGROUND: Knee pain has a lifetime prevalence of up to 45%, and as many as 31% of individuals with knee pain will consult a general practitioner. Roughly 5% of these individuals will undergo a tibial meniscectomy and many more will undergo partial meniscectomy or meniscus repair. Determining which of these individuals is appropriate for surgical consult depends on clinical examination findings. METHODS AND MEASURES: We searched MEDLINE, CINAHL, and SPORTDiscus from1966 to August 2006 and extracted all English- and German-language studies that reported the diagnostic accuracy of individual physical examination tests for a torn meniscus. We retrieved data regarding true positives, false positives, true negatives, and false negatives to create 2-by-2 tables for each article and test. Like tests were then subjected to meta-analysis and subanalysis. Cochran Q test and the 12 statistic were used to examine for the presence of heterogeneity and the extent of the effect of heterogeneity, respectively. A qualitative analysis was also performed using the QUADAS tool. RESULTS: Eighteen studies qualified for the final analyses. Three physical examination tests (McMurray's, Apley's, and joint line tenderness) were examined in more than 7 studies and had enough data to consider meta-analysis. However, study results were heterogeneous. Pooled sensitivity and specificity were 70% and 71% for McMurray's, 60% and 70% for Apley's, and 63% and 77% for joint line tenderness. Large between-study differences could not be explained by prevalence, study quality, or how well an index test was described. CONCLUSIONS: No single physical examination test appears to accurately diagnose a torn tibial meniscus and the value of history plus physical examination is unknown. Differences between studies in diagnostic performance remain unexplained, presumably due to local differences in the way the tests are defined, performed, and interpreted. We recommend a more standardized approach to performing and interpreting these tests and the development of a clinical prediction rule to aid clinicians in the diagnosis of a torn tibial meniscus.

In or out? Methodological considerations for including and excluding findings from a meta-analysis of predictors of antiretroviral adherence in HIV-positive women.

AIM: This paper is a discussion detailing the decisions concerning whether to include or exclude findings from a meta-analysis of report of quantitative studies of antiretroviral adherence in HIV-positive women. BACKGROUND: Publication constraints and the absence of reflexivity as a criterion for validity in, and reporting of, quantitative research preclude detailing the many judgements made in the course of a meta-analysis. Yet, such an accounting would assist researchers better to address the unique challenges to meta-analysis presented by the bodies of research they have targeted for review, and to show the subjectivity, albeit disciplined, that characterizes the meta-analytic process. DATA SOURCES: Data were 29 published and unpublished studies on antiretroviral adherence in HIV-positive women of any race/ethnicity, class, or nationality living in the United States of America. The studies were retrieved between June 2005 and January 2006 using 40 databases. REVIEW METHODS: Findings were included if they met the statistical assumptions of meta-analysis, including: (1) normal distribution of observations; (2) homogeneity of variances; and (3) independence of observations. RESULTS: Relevant studies and findings were excluded because of issues related to differences in study design, different operationalizations of dependent and independent variables, multiple cuts from common longitudinal data sets, and presentation of unadjusted and adjusted findings. These reasons led to the exclusion of 73% of unadjusted relationships and 87% of adjusted relationships from our data set, leaving few findings to synthesize. CONCLUSION: Decisions made during research synthesis studies may result in more information losses than gains, thereby obliging researchers to find ways to preserve findings that are potentially valuable for practice.

The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF).

Acute heart failure syndromes (AHFS) are related to several diseases affecting not only the heart but also the kidneys and blood vessels. Emerging evidence indicates that myocardial injury may also play a role in the pathophysiology of AHFS, as suggested by increased levels of markers of injury, such as cardiac troponin (cTn). Although cTn is a known prognostic marker, the release of cTn during hospitalization has not been evaluated prospectively with serial measures. We prospectively evaluated patterns of cTn release by conducting serial measures of cTnI and cTnT in patients hospitalized for AHFS. This study enrolled 51 patients with AHFS who were admitted with worsening heart failure (HF) and a history of coronary artery disease (CAD) in whom an acute coronary event was not suspected. Levels of cTnI and cTnT were measured at 8, 32, 56, and 80 hours after study entry. At baseline, 73.9% of patients had detectable cTnI, and 43.5% had detectable cTnT levels. The median concentrations of cTnI and cTnT were unchanged from 0 to 32 hours, increased from 32 to 56 hours, then either plateaued (cTnT) or decreased to baseline (cTnI). Of the 26 patients who had no detectable cTn levels at baseline, 2 (7.7%) developed detectable cTnT and 5 (41.7%) developed detectable cTnI release during hospitalization. Detectable levels of cTn at baseline were related to short-term clinical events. In this study of patients with CAD in whom an acute coronary event was not suspected, most had detectable levels of cTn present at admission, and some patients developed cTn release during hospitalization. Because cTn release may be a marker for myocardial injury, this study raises the possibility that injury occurred in most patients admitted with AHFS. Therefore, the goal of therapy for AHFS should be not only to improve symptoms and hemodynamics but also to salvage myocardium. Accordingly, therapies for AHFS that are aimed at improving hemodynamics may affect long-term prognosis by either injuring or salvaging myocardium.

Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study).

In a nonrandomized feasibility study of therapeutic hypothermia in acute myocardial infarction, 18 patients were treated with endovascular cooling (Alsius, Irvine, California) as adjunctive therapy to primary percutaneous coronary intervention to assess measures of infarct size (area under the curve creatinine kinase-MB and technetium-99m single-photon emission computed tomography sestamibi) and the quality of myocardial perfusion (continuous ST-segment monitoring). Periprocedural endovascular cooling successfully decreased core body temperature (median 33.5 degrees C) and was well tolerated, which supports the evaluation of adjunctive hypothermia in pivotal trials to limit infarct size and decrease reperfusion injury.

Tocolytic treatment for the management of preterm labor: a review of the evidence.

OBJECTIVE: Preterm labor is often a prelude to early births and the significant attendant burden of infant morbidity and mortality. Treatment consists of bedrest, hydration, pharmacologic interventions, and combinations of these. We systematically reviewed the effectiveness of tocolytics to stop uterine contractions (first-line therapy) or maintain quiescence (maintenance therapy). Our objective was to evaluate the evidence on the benefits and harms of five classes of tocolytic therapy for treating uterine contractions related to preterm labor--beta-mimetics, calcium channel blockers, magnesium, nonsteroidal anti-inflammatory agents, and ethanol. STUDY DESIGN: Reports of randomized controlled trials and other study designs in English, French, and German identified from searches of MEDLINE, EMBASE, specialized databases, bibliographies of review articles, unpublished literature, and discussions with investigators in the field were identified. Studies on women with preterm labor between 1966 and February 1999 that met our inclusion criteria were included. Through dual review, we abstracted the following information: study design and masking; definitions of preterm labor and successful tocolysis; patient inclusion/exclusion characteristics; patient demographic characteristics; drug and cointerventions; and numerous birth, maternal, and neonatal outcome measures. RESULTS: Of the 256 articles evaluated, we abstracted data from 60 first-line and 15 maintenance studies. Of these, 16 first-line and 8 maintenance studies met more stringent requirements for meta-analyses. Studies of first-line tocolysis (grade Fair) reveal a mixed outcome pattern with small improvement in pregnancy prolongation and birth at term relative to placebo. Data were insufficient to show directly a beneficial effect on neonatal morbidity or mortality. Ethanol was less beneficial than, and beta-mimetics were not superior to, other tocolytic options. Maintenance tocolytics (grade Poor) showed no improvements in birth or infant outcomes relative to placebo; these results were confirmed through meta-analysis. In contrast to other tocolytic treatments, maternal harms from beta-mimetics were rated High; all tocolytics were rated as Low risk for short-term neonatal harms. CONCLUSIONS: Management of uterine contractions with first-line tocolytic therapy can prolong gestation. Among the tocolytics, however, beta-mimetics appear not to be better than other drugs and pose significant potential harms for mothers; ethanol remains an inappropriate therapy. Continued maintenance tocolytic therapy has little or no value.

Evaluation of a tool to categorize patients by reading literacy and computer skill to facilitate the computer-administered patient interview.

Past efforts to collect clinical information directly from patients using computers have had limited utility because these efforts required users to be literate and facile with the computerized information collecting system. In this paper we describe the creation and use of a computer-based tool designed to assess a user's reading literacy and computer skill for the purpose of adapting the human-computer interface to fit the identified skill levels of the user. The tool is constructed from a regression model based on 4 questions that we identified in a laboratory study to be highly predictive of reading literacy and 2 questions predictive of computer skill. When used in 2 diverse clinical practices the tool categorized low literacy users so that they received appropriate support to enter data through the computer, enabling them to perform as well as high literacy users. Confirmation of the performance of the tool with a validated reading assessment instrument showed a statistically significant difference (p=0.0025) between the two levels of reading literacy defined by the tool. Our assessment tool can be administered through a computer in less than two minutes without requiring any special training or expertise making it useful for rapidly determining users' aptitudes.