Lori A. Orlando

Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers for Treating Essential Hypertension

Context Are angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) more effective for treating essential hypertension? Contribution This systematic review of trials that directly compared ACE inhibitors and ARBs in adults with essential hypertension found good evidence that the agents had similar long-term effects on blood pressure. There were no consistent differential effects for mortality, cardiovascular events, progression to diabetes, left ventricular function, or kidney disease. Cough was more frequent with ACE inhibitors than ARBs. Implication Both ACE inhibitors and ARBs have similar effects on blood pressure and may not have differential effects on other clinical outcomes, although ACE inhibitors do cause cough more often than ARBs. The Editors More than 65 million U.S. adultsapproximately one thirdhave hypertension. In addition to being the leading attributable risk factor for death throughout the world (1), hypertension results in substantial illness due to its effect on several target organs, including the brain, eyes, heart, arteries, and kidneys. Despite the high rate of morbidity and mortality attributable to hypertension, control remains suboptimal (2). In addition to several effective nonpharmacologic interventions, many individuals require antihypertensive medication to lower blood pressure and often require several medications together (2). Among the most common of the many choices in antihypertensive therapy are those aimed at inhibiting the reninangiotensinaldosterone (renin) system. Currently, renin system inhibitors include angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Although clinicians regard ACE inhibitors and ARBs as effectively equivalent, it is not clear whether this is appropriate. For example, ACE inhibitors do not entirely block production of angiotensin II because of other, unaffected converting enzymes. Also, ACE inhibitors are associated with well-known adverse events not shared by ARBs, including cough (estimated incidence, 5% to 20%) and the possibly related phenomenon of angioedema (estimated incidence, 0.1% to 0.2%) (3). Although both ACE inhibitors and ARBs are highly effective in lowering blood pressure among patients with essential hypertension (4, 5), their comparative effectiveness and the relative advantages and disadvantages of ACE inhibitors versus ARBs are unknown. This review summarizes the evidence on the comparative long-term benefits and harms of ACE inhibitors versus ARBs for treating essential hypertension in adults. The full technical report was commissioned by the Agency for Healthcare Research and Quality (6). Methods We developed and followed a standardized protocol for all steps of the review. Data Sources and Searches We searched MEDLINE (1966 to week 3 of May 2006) and the Cochrane Central Register of Controlled Trials (Issue 2, 2006) for studies published in English after 1988, using terms for drug interventions, hypertension, and study design. We also reviewed bibliographies submitted by pharmaceutical companies to the Scientific Resource Center for the Agency for Healthcare Research and Qualitys Effective Health Care Program, reference lists of relevant review articles, and citations identified by reviewers of the draft report. For the current review, we updated our MEDLINE search to August 2007 to identify new head-to-head trials that reported blood pressure outcomes and major cardiovascular events. Results from the newly identified studies (721) were consistent with the evidence described in the full technical report and are not presented here. Study Selection We included comparative clinical studies of any design (including randomized, controlled trials and nonrandomized, controlled trials; cohort studies; and casecontrol studies) that provided direct comparisons of ACE inhibitors versus ARBs at 12 weeks or more after the initial intervention. In addition to simple comparisons of a single ACE inhibitor versus a single ARB, we included studies with grouped comparisons (such as a specific ARB versus ACE inhibitors or unspecified ARBs versus unspecified ACE inhibitors) and comparisons in which the same drug was administered with an ACE inhibitor versus that drug with an ARB (for example, losartan and hydrochlorothiazide vs. enalapril and hydrochlorothiazide). We excluded studies with comparisons in which the drugs administered with an ACE inhibitor differed from those administered with an ARB (for example, enalapril and manidipine vs. irbesartan and hydrochlorothiazide). We included studies with treatment protocols that permitted the addition of other antihypertensive medications during the trial, provided that the co-intervention protocols were the same in the ACE inhibitor and ARB treatment groups. Outcomes we considered included blood pressure control, adherence, quality of life, several intermediate outcomes, and harms. We excluded studies with fewer than 20 total patients in the ACE inhibitor and ARB treatment groups and focused on studies of adults (18 years of age) with essential hypertension, as defined by the study authors. We also evaluated studies of ARBs versus other (nonACE inhibitor) comparators and ACE inhibitors versus other (non-ARB) comparators, which were to be considered in case too few direct head-to-head trials were identified for outcomes of interest. Appendix 1 contains the details of how we identified and reviewed indirect comparison studies. Data Extraction and Quality, Applicability, and Strength of Evidence Assessments One author extracted data from each study, which were confirmed by another author. Extracted information included study design; interventions; population characteristics; recruitment setting; inclusion and exclusion criteria; numbers of participants screened, eligible, enrolled, and lost to follow-up; and results for each outcome. We used predefined criteria adapted from those developed by the U.S. Preventive Services Task Force (22) and the Centre for Reviews and Dissemination in the United Kingdom (23) to assess the quality of individual studies as good, fair, or poor, and we noted important limitations on internal validity for studies rated as fair or poor. The applicability of individual studies was assessed by noting the most important potential limitations (up to 3) in a studys applicability from among the list described by Rothwell (24), as adapted by the Scientific Resource Center (Appendix 2). Quality and applicability assessments are detailed for individual studies in the evidence tables included in the full report (6). Finally, we assessed the strength of the body of evidence for each key question as high, moderate, low, or very low by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (25). Data Synthesis and Analysis Given that many studies did not have the statistical power to determine equivalence for relevant outcomes, we considered pooling (without regard to the specific drug within the ACE inhibitor or ARB class) to overcome a type II error. In evaluating direct comparison studies for potential data synthesis, we primarily considered clinical homogeneity. In general, we considered groups of studies as suitable for quantitative synthesis when we identified at least 4 clinically and relatively similar studies that assessed the same outcome. We used additional and more detailed criteria to determine suitability for pooling of indirect comparisons, as such comparisons are tenuous (Appendix 1). We did not attempt to pool direct and indirect comparison studies in a single analysis, primarily because we did not identify a sufficient number of clinically similar indirect comparison studies to analyze. When we pooled studies, we used the random-effects model for the primary analysis and the fixed-effect model for sensitivity analysis. We stratified analyses by study design, separating randomized, controlled trials from observational studies. We performed all analyses by using Comprehensive Meta-analysis, version 2 (Biostat, Englewood, New Jersey). For count outcomes, we calculated summaries of the relative effect (odds ratios) and absolute effect (risk difference). We chose the Peto method for analyzing data on cough and withdrawals due to adverse events because event rates were low and treatment groups were not substantially imbalanced, conditions under which this method is the least biased and most powerful (26). This method also allows inclusion of studies with zero events in 1 group with no continuity correction. For data on rates of successful monotherapy, we used risk differences because event rates were high, which makes the assumption of a constant odds ratio unreasonable. Role of the Funding Source The Agency for Healthcare Research and Quality formulated the initial study questions and reviewed and commented on planned methods, data analysis, and the draft report. The funding source did not participate in the search of the literature, determination of study eligibility, or evaluation of individual studies. Results Of 1185 citations, 69 reports (61 distinct studies) directly compared ACE inhibitors with ARBs (Figure 1). Forty-seven studies were randomized, controlled trials; 1 was a nonrandomized, controlled trial; 9 were retrospective cohort studies; 2 were prospective cohort studies; 1 was a cross-sectional cohort study; and 1 was a casecontrol study. Table 1 shows the numbers of studies that compared different agents. Enalapril was the most frequently studied ACE inhibitor (24 studies), and losartan the most frequently studied ARB (19 studies). Most studies were relatively short-term; 19 followed patients for 12 weeks, and 21 followed patients between 12 weeks and 6 months. Most studies excluded patients with secondary causes of hypertension, as well as patients with recent acute events, such as myocardial infarction or stroke. Table 2 summarizes the number

Systematic review: reliability of compendia methods for off-label oncology indications.

The U.S. Food and Drug Administration (FDA) approves drugs for specific uses, yet physicians routinely prescribe FDA-approved drugs for uses other than those for which they received approval (1); such uses are known as off-label indications. Off-label prescribing is common across medical disciplines; however, it is critical in oncology, in which effective treatment options are often limited, prognoses are grim, and submission of FDA applications for every combination of agent and cancer is impractical. In 1991, a U.S. General Accounting Office study (2) reported that up to 33% of all anticancer drug prescriptions were written for off-label indications. By 2005, the National Comprehensive Cancer Network estimated that 50% to 75% of all uses of cancer therapy were off-label (3). The Social Security Act, section 1861(t)(2)(B)(ii)(I) and (II), within the Omnibus Budget Reconciliation Act of 1993 (4), stipulates the Medicare insurability of anticancer drugs and biologics for off-label uses. This statute recognizes certain compendia as authoritative sources for determining a medically accepted indication of drugs and biological agents, unless the Secretary of Health and Human Services determines otherwise. The statute originally designated 3 compendia: American Medical Association Drug Evaluations, American Hospital Formulary Service Drug Information (5), and United States Pharmacopeia Drug Information for the Health Professional (6). Although the statute pertained specifically to Centers for Medicare & Medicaid Services (CMS), most other payers and state legislatures have followed suit (7). The list of approved compendia has shifted over the past 15 years. American Medical Association Drug Evaluations was discontinued, and United States Pharmacopeia Drug Information for the Health Professional subsumed its contents. United States Pharmacopeia Drug Information for the Health Professional was then discontinued in 2007, and its contents were rolled into a successor, DrugPoints. In 2008, CMS added Clinical Pharmacology, DRUGDEX, and National Comprehensive Cancer Network Drugs and Biologics Compendium to its list of approved compendia, bringing the total to 5 (8). In response to concerns about the influence of compendia, CMS proposed various changes, including review of currently approved compendia, additional compendia approval, and an annual review process. To inform policy discussions, they commissioned the Agency for Healthcare Research and Quality to sponsor our project exploring the extent to which compendia provide comprehensive, evidence-based, and timely information for guiding off-label prescribing of cancer drugs. Methods Our study had 4 components: comparative descriptions of each compendiums stated methods for including new, off-label indications of FDA-approved drugs; systematic literature review for 14 selected off-label indications in 2006; an updated comparison for 1 indication in 2008; and analysis of each compendiums content and citations against their stated methods and the evidence identified in our systematic reviews. Comparative Description of Methods Used by Compendia To better understand how compendia develop their content, we compared 6 compendia that we chose through discussions with 10 oncology pharmacists and oncologists at Duke University and Tufts Medical Centers. We confirmed the list through discussions with the Agency for Healthcare Research and Quality, CMS, and financial officers at Duke University Medical Center. Our final compendia list included American Hospital Formulary Service Drug Information (5), United States Pharmacopeia Drug Information for the Health Professional (6), DRUGDEX Information System (United States Pharmacopeia Drug Information for the Health Professional and DRUGDEX, both available through Thomson Reuters) (9), Drug Facts and Comparisons (10), National Comprehensive Cancer Network Drugs and Biologics Compendium (11), and Clinical Pharmacology (12). This list includes the compendia approved by CMS as well as 2 nonapproved compendia. These compendia list more than 40000 drugs, and their editors are generally pharmacologists with training in research and evidence synthesis. In 2006, we gathered information on each compendiums methods by abstracting descriptive information from publicly available sources, conducting a 1-hour telephone interview with a senior editor from each compendium, and allowing the editors to respond to a methods table that summarized the information collected in the interview. We developed a list of evaluation criteria which we used to compare published methods and guide interviews. We then compared each compendiums methods with evaluation criteria and summarized the results. In 2008, we repeated the data abstraction to determine whether the compendia had updated their publicized methods. We did not include DrugPoints in the 2008 review because it differed structurally from the other compendia and could not be directly compared. Literature Review of Evidence for 14 Off-Label Indications We selected off-label indications for 14 agent and cancer combinations that included both newer and older agents, common and rare types of cancer, and biologics and drugs. In 2006, we systematically searched MEDLINE, the Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology annual meeting abstracts (2004 and 2005) to identify English-language studies in humans. We included prospective clinical trials (phases I to III), case reports, and retrospective case series that reported tumor response, survival, quality of life, symptoms, and adverse effects. We excluded narrative reviews and studies that described only predictors of response, pharmacokinetics, or nonhuman results. For eligible studies, 1 reviewer abstracted data into evidence tables and a second reviewer verified the completed tables. For each agent and cancer combination, we created a summary table that listed the number of articles identified by study design and key outcomes. We scored identified studies by design (for example, phase I to III), size, and outcomes reported (for example, tumor response, survival, quality of life, or adverse effects). Our intention was not to expose the compendiawhich perform a vital function in oncologybut rather to examine their methods and the resulting comprehensiveness of their contents. We therefore did not score the evidence included in the compendia according to classic quality criteria. Instead, we adopted a conservative approach to content evaluation that entailed a simple count of independent studies, presentations of data, and other metrics but did not include evaluation of the quality and validity of the studies themselves. We used study design as a proxy for quality and validity, with phase III studies considered generally more valid than phase I or II studies. Update of 1 Agent and Cancer Combination In 2008, we repeated the systematic review for a single agent and cancer combination (gemcitabine for bladder cancer) by using the same methods, except we sought 2006 and 2007 conference abstracts. We chose the gemcitabine for bladder cancer indication because gemcitabine has been FDA-approved for longer than the other reviewed agents; gemcitabine has been widely studied (with the largest number of citations in our 2006 review); and, of the 3 gemcitabine combinations included, gemcitabine for bladder cancer had the fastest-evolving evidence base. This combination thus afforded compendia the most opportunity to demonstrate improvement. Analysis of Compendium Content Against Evaluation Criteria In 2006, we abstracted data for each of the 14 agent and cancer combinations from each of the 6 compendia. We evaluated all available versions (print and electronic) of the 6 compendia in 2006 but recorded data from the most current and complete version; in all cases, this was an electronic version. Data included whether the indication was explicitly stated; how the indication was graded; and comments on further refinement regarding the stage of cancer, treatment timing, route of administration, and use of monotherapy or combination therapy. We recorded outcomes mentioned specifically for the off-label use; toxicity data; presence of citations to evidence specifically regarding the off-label indication; number, identity, and years of citations; and time since any updates to the monograph or entry. We stratified publications cited in the compendia by study design, noting abstracts separately, and tabulated whether each compendium cited each publication; we compared the results with those of our systematic review. We updated this process in 2008 for the gemcitabine for bladder cancer indication. Role of the Funding Source The CMS funded the initial 2006 report through the Agency for Healthcare Research and Qualitys Evidence-Based Practice Center program. These agencies participated in formulating questions, reviewing the list of agent and cancer combinations, and commenting on report findings. The 2008 update of the report was unfunded. The agencies had no role in the writing or approval of the manuscript. Results Comparison of Stated Methods Used by Compendia All compendia described their scope and editorial policies, which did not change between the 2006 and 2008 reviews (Appendix Table 1). Because United States Pharmacopeia Drug Information for the Health Professional was discontinued in 2007, our results do not include that compendium even though it was part of the 2006 review. Here, we focus our evaluation on frequency of updates, use of available evidence, and transparency of decision-making processes. Appendix Table 1. Stated Methods of Selected Compendia Compendia had different update cycles for electronic versions, which varied from daily to quarterly (Table 1). Several compendia published multiple electronic editions; these differed in content and update schedules. Compendia did not always provide revision dates for drug m

The IGNITE network: a model for genomic medicine implementation and research

BackgroundPatients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility.MethodsTo address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches.ResultsThis paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years.ConclusionsThe IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.

Meta-analysis: The detection of pancreatic malignancy with positron emission tomography

Background : Several factors contribute to the high mortality of pancreatic cancer, including limitations of diagnostic imaging.

Genomic risk profiling: attitudes and use in personal and clinical care of primary care physicians who offer risk profiling.

ABSTRACTBACKGROUNDGenomic risk profiling involves the analysis of genetic variations linked through statistical associations to a range of disease states. There is considerable controversy as to how, and even whether, to incorporate these tests into routine medical care.OBJECTIVETo assess physician attitudes and uptake of genomic risk profiling among an ‘early adopter’ practice group.DESIGNWe surveyed members of MDVIP, a national group of primary care physicians (PCPs), currently offering genomic risk profiling as part of their practice.POPULATIONAll physicians in the MDVIP network (N = 356)RESULTSWe obtained a 44% response rate. One third of respondents had ordered a test for themselves and 42% for a patient. The odds of having ordered personal testing were 10.51-fold higher for those who felt well-informed about genomic risk testing (p < 0.0001). Of those who had not ordered a test for themselves, 60% expressed concerns for patients regarding discrimination by life and long-term/disability insurers, 61% about test cost, and 62% about clinical utility. The odds of ordering testing for their patients was 8.29-fold higher among respondents who had ordered testing for themselves (p < 0.0001). Of those who had ordered testing for patients, concerns about insurance coverage (p = 0.014) and uncertain clinical utility (p = 0.034) were associated with a lower relative frequency of intention to order testing again in the future.CONCLUSIONSOur findings demonstrate that respondent familiarity was a key predictor of physician ordering behavior and clinical utility was a primary concern for genomic risk profiling. Educational and interpretive support may enhance uptake of genomic risk profiling.

Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors

Purpose: Cytochrome P450 (CYP450) enzymes metabolize selective serotonin reuptake inhibitor (SSRI) drugs used in treatment of depression. Variants in these genes may impact treatment efficacy and tolerability. The purpose of this study was 2-fold: to systematically review the literature for evidence supporting CYP450 genotyping to guide SSRI treatment for major depression, and, where evidence is inadequate, to suggest future research.Methods: We searched MEDLINE® and other databases for studies addressing five key questions suggested by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Eligibility criteria were defined, and studies were reviewed independently by paired researchers. A conceptual model was developed to guide future research.Results: Review of 1200 abstracts led to the final inclusion of 37 articles. The evidence indicates relatively high analytic sensitivity and specificity of tests detecting a subset of polymorphisms of CYP2D6, 2C19, 2C8, 2C9, and 1A1. We found marginal evidence regarding a clinical association between CYP450 variants and SSRI metabolism, efficacy, and tolerability in the treatment of depression.Conclusions: Current evidence does not support the use of CYP450 genotyping to guide SSRI treatment of patients with depression. Studies are proposed that will effectively guide decision-making in the area of CYP450 testing in depression, and genetic testing more generally.

Chronic Hypergastrinemia: Causes and Consequences

The hormone gastrin plays 2 important roles in gastrointestinal physiology—1 as a major factor in meal-stimulated gastric acid secretion and the other as a trophic hormone for epithelial and enterochromaffin cells. These roles are exaggerated to the point of pathology under conditions of chronic hypergastrinemia as exemplified by the Zollinger-Ellison syndrome and pernicious anemia. More recently, the concern about the potential risk of chronic hypergastrinemia has risen because of the widespread use of proton pump inhibitors for maintenance therapy in reflux esophagitis. For this reason, we present a concise overview of the origin, causes, and potential risks of chronic hypergastrinemia.

Cost effectiveness analysis of hemiarthroplasty and total shoulder arthroplasty

BACKGROUND Total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) are two viable surgical treatment options for glenohumeral osteoarthritis. Recent systematic reviews and randomized trials suggest that TSA, while more costly initially, may have superior outcomes with regard to pain, function and quality of life with lower revision rates. This study compared the cost-effectiveness of TSA with HA. METHODS A Markov decision model was constructed for a cost-utility analysis of TSA compared to HA in a cohort of 64-year-old patients. Outcome probabilities and effectiveness were derived from the literature. Costs were estimated from the societal perspective using the national average Medicare reimbursement for the procedures in 2008 US dollars. Effectiveness was expressed in quality-adjusted life years (QALYs) gained. Principal outcome measures were average incremental costs, incremental effectiveness, incremental QALYs, and net health benefits. RESULTS In the base case, HA resulted in a lower number of average QALYs gained at a higher average cost to society and was, therefore, dominated by the TSA strategy for the treatment of glenohumeral osteoarthritis. The cost effectiveness ratio for TSA and HA were

Quality of family history collection with use of a patient facing family history assessment tool

957/QALY and

Implementing Family Health History Risk Stratification in Primary Care: Impact of Guideline Criteria on Populations and Resource Demand

1,194/QALY respectively. Sensitivity analysis revealed that if the utility of TSA is equal to, or revision rate lower than HA, TSA continues to be a dominant strategy. CONCLUSION Total shoulder arthroplasty with a cemented glenoid is a cost-effective procedure, resulting in greater utility for the patient at a lower overall cost to the payer. These findings suggest that TSA is the preferred treatment for certain populations from both a patient and payer perspective.