David C. Rhew

Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction

Angiotensin-receptor blockers (ARBs) were first introduced into the marketplace in the early 1990s and have been used to treat various conditions, including hypertension and heart failure (1). Angiotensin-receptor blockers reduce afterload and increase cardiac output in heart failure (2, 3), similar to the mechanism of action seen with angiotensin-converting enzyme (ACE) inhibitors, while also reversing left ventricular remodeling (4). The benefits of ACE inhibitors might also be partly attributed to prevention of the formation of inflammatory cytokines by angiotensin II (5-7). A study has suggested that ARBs could share similar anti-inflammatory properties (6). The American College of Cardiology/American Heart Association (ACC/AHA) (8) and the Heart Failure Society of America (HFSA) (9) recommend that ACE inhibitors be preferred over ARBs for patients with heart failure and left ventricular systolic dysfunction but state that ARBs may be considered for patients who are intolerant of ACE inhibitors. Furthermore, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) (10) and the Centers for Medicare & Medicaid Services (CMS) (11) have defined quality indicators for patients with heart failure and acute myocardial infarction (MI), which currently include administering ACE inhibitors as first-line therapy for patients with an ejection fraction less than 0.40. Neither JCAHO nor the CMS has defined quality indicators for ARB administration, and they have not recognized ARB therapy as an acceptable reason for not administering ACE inhibitors. This may have occurred partly because of the inconclusive and conflicting nature of the data in previously published randomized, controlled trials about the effect of ARBs on death and hospitalizations. A 2000 systematic review by Flather and colleagues (12) showed that ACE inhibitors result in lower mortality and heart failure hospitalizations as compared with placebo in patients with heart failure and left ventricular systolic dysfunction. However, a 2002 meta-analysis by Jong and colleagues (13) included randomized, controlled trials published up to May 2001 and showed no statistically significant difference in mortality or heart failure hospitalization rates between ARBs and placebo in patients with heart failure and left ventricular systolic dysfunction. Since May 2001, the largest series of randomized, controlled trials evaluating ARBs in chronic heart failure, Candesartan in Heart FailureAssessment of Reduction in Mortality and Morbidity (CHARM) (14-17), has been published. In the CHARM-Alternative trial (15), patients who were intolerant of ACE inhibitors were randomly assigned to candesartan or placebo. The results showed that candesartan was associated with a statistically significant reduction in heart failure hospitalization but only a nonstatistically significant reduction in all-cause mortality. Data from randomized, controlled trials evaluating ARBs and ACE inhibitors in patients with high-risk acute MI (defined as acute MI complicated by heart failure) have also been recently published in the Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) (18) and Valsartan in Acute Myocardial Infarction (VALIANT) trial (19). Researchers have recommended that meta-analyses be continually updated as new and relevant randomized, controlled trials are published since meta-analyses may quickly become outdated (20, 21). The objective of this meta-analysis is to incorporate data from recently published randomized, controlled trials into the pool of evidence and to determine whether recently published research affects the statistical significance of efficacy outcomes for the use of ARBs in chronic heart failure and high-risk acute MI. Methods Data Sources We reviewed the medical literature to identify studies evaluating the efficacy of ARBs in patients with chronic heart failure and high-risk acute MI. We searched for articles from the following medical bibliographic databases: Cochrane Central Register of Controlled Trials (third quarter 2003), Cochrane Database of Systematic Reviews (third quarter 2003), Cumulative Index to Nursing and Allied Health Literature (1982 to November week 1 2003), Database of Abstracts of Reviews of Effects (third quarter 2003), HealthSTAR (1975 to October 2003), and MEDLINE (1966 to present). The search included terms related to heart failure and acute MI (cardiac failure, cardiac insufficiency, congestive heart failure, coronary disease, heart failure, and myocardial infarction) that were combined with terms related to ARBs (angiotensin receptors, candesartan, elisartan, embusartan, eprosartan, forasartan, irbesartan, losartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan, and zolasartan) using Boolean operators and syntax that were appropriate for each database. We also manually searched references from selected clinical trials and review articles. Finally, we reviewed abstracts from the 2002 and 2003 conference proceedings of the ACC, AHA, Canadian Cardiovascular Society (CCS), European Society of Cardiology (ESC), and HFSA. Study Selection We followed a written protocol with explicit article selection criteria. We rejected articles at the title and abstract stage if they were not randomized, controlled trials; were not written in English; did not address patients with chronic heart failure or high-risk acute MI; did not compare ARBs versus an appropriate control group (ARBs vs. placebo, ARBs vs. ACE inhibitors, or ARB plus ACE inhibitor combinations vs. ACE inhibitors alone); or did not enroll human participants. We subjected the full text of remaining articles to the same criteria and rejected them if all-cause mortality and heart failure hospitalization outcomes were not reported or the follow-up duration was less than 4 weeks. Data Extraction Two reviewers used a standardized form to independently extract information on study design, sample characteristics, sample size, intervention strategies, outcome measures, and other study characteristics from included randomized, controlled trials. We assessed the methodologic quality of randomized, controlled trials by using a scoring system developed by Jadad and colleagues (22). We obtained raw data, when available, for all-cause mortality and heart failure hospitalization outcomes from intention-to-treat analyses. Heart failure hospitalization was defined as the number of patients with 1 or more postrandomization admissions for heart failure, for complications from treatment of heart failure, or for management of comorbid conditions associated with heart failure. For studies in which patients were randomly assigned to 1 of several dosage groups of the same study medication, we pooled outcomes from those groups for the analysis. We resolved discrepancies through discussion and consensus opinion or by contacting the corresponding author of the original clinical trial. Statistical Analysis We calculated values for agreement by using the methods described by Fleiss (23). We calculated an odds ratio for each study outcome to allow for pooling of similar outcomes. For studies in which 1 of the randomization groups had no events, we used a continuity correction factor (that is, adding 0.5 to each cell) to avoid dividing by 0 (23). We reported results as the pooled odds ratio with 95% CIs. We calculated pooled odds ratios and 95% CIs for random-effects models on the basis of the methods of DerSimonian and Laird (24), and we used the MantelHaenszel (25) method for fixed-effects models. We used a chi-square test to assess heterogeneity. We sorted data into 3 main comparison groups: ARBs versus placebo, ARBs versus ACE inhibitors, and ARB and ACE inhibitor combinations versus ACE inhibitors alone (including comparisons of ARBs vs. placebo for studies in which patients received ACE inhibitors in both groups). We performed sensitivity analyses for each group to determine how the prespecification of end points influenced results. In the presence of statistical heterogeneity, defined as a chi-square test P value less than 0.10, we analyzed the data by using random-effects models. Otherwise, we used fixed-effects models. The P value threshold for statistical significance was set at 0.05 for effect sizes. We performed statistical calculations by using Stata, version 8.1 (Stata Corp., College Station, Texas), and RevMan, version 4.2.6 (The Cochrane Collaboration, Oxford, United Kingdom). We generated a funnel plot (by using Excel 2000 [Microsoft Corp., Redmond, Washington]) of randomized, controlled trials with estimable odds ratios for all-cause mortality in chronic heart failure to assess the presence of publication bias. We plotted the inverse of the standard error of the natural logarithm of the odds ratio against the natural logarithm of the odds ratio. Role of the Funding Source The funding source had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Data Synthesis Included Studies Figure 1 presents an article flow diagram. From the initial search of all medical bibliographic databases, we identified 1603 articles. After we excluded duplicates, 1158 unique records remained. On the basis of prespecified exclusion criteria, we rejected 1074 articles during title and abstract review. The value from the title and abstract review was 0.76. We rejected another 62 articles during the full-text review, yielding a total of 22 articles. We excluded 1 study (26) from the pooled analysis because we could not reconcile the distribution of patient deaths across study groups despite communication with the corresponding author. A manual search of relevant articles revealed 2 additional phase III randomized, controlled trials (27) whose raw data were presented in a meta-analysis, as well as the VALIANT study (19), which was published on the day of our search. Our search of abstracts f

Association between Protease Inhibitor Use and Increased Cardiovascular Risk in Patients Infected with Human Immunodeficiency Virus: A Systematic Review

Some studies have shown that currently available protease inhibitors (PIs) are associated with an increased risk of cardiovascular disease. We have systematically reviewed the published literature and conference abstracts for studies evaluating cardiovascular risk factors and events in patients receiving highly active antiretroviral therapy, with and without PIs. The majority of studies showed that the use of PIs was associated with increased levels of total cholesterol (36 [75%] of 48 studies), triglycerides (35 [73%] of 48 studies), and low-density lipoprotein (12 [100%] of 12 studies). PI use was often associated with morphological signs of cardiovascular disease, such as increased carotid intima thickness or atherosclerotic lesions (7 [88%] of 8 studies). Finally, 2 (67%) of 3 long-term observational studies that met our inclusion criteria demonstrated an association between use of PIs and subsequent myocardial infarction. The benefits of the currently available PIs should be balanced against the long-term risk of cardiovascular disease.

Improving Pneumococcal Vaccine Rates: Nurse Protocols Versus Clinical Reminders

AbstractOBJECTIVE: To compare the effectiveness of three interventions designed to improve the pneumococcal vaccination rate. DESIGN: A prospective controlled trial. SETTING: Department of Veterans Affairs ambulatory care clinic. PATIENTS/PARTICIPANTS: There were 3,502 outpatients with scheduled visits divided into three clinic teams (A, B, or C). INTERVENTIONS: During a 12-week period, each clinic team received one intervention: (A) nurse standing orders with comparative feedback as well as patient and clinician reminders; (B) nurse standing orders with compliance reminders as well as patient and clinician reminders; and (C) patient and clinician reminders alone. Team A nurses (comparative feedback group) received information on their vaccine rates relative to those of team B nurses. Team B nurses (compliance reminders group) received reminders to vaccinate but no information on vaccine rates. MEASUREMENTS AND MAIN RESULTS: Team A nurses assessed more patients than team B nurses (39% vs 34%, p=.009). However, vaccination rates per total patient population were similar (22% vs 25%, p=.09). The vaccination rates for both team A and team B were significantly higher than the 5% vaccination rate for team C (p<.001). CONCLUSIONS: Nurse-initiated vaccine protocols raised vaccination rates substantially more than a physician and patient reminder system. The nurse-initiated protocol with comparative feedback modestly improved the assessment rate compared with the protocol with compliance reminders, but overall vaccination rates were similar.

Relationship between organizational factors and performance among pay-for-performance hospitals.

ABSTRACTBACKGROUNDThe Centers for Medicare & Medicaid Services (CMS)/Premier Hospital Quality Incentive Demonstration (HQID) project aims to improve clinical performance through a pay-for-performance program. We conducted this study to identify the key organizational factors associated with higher performance.METHODSAn investigator-blinded, structured telephone survey of eligible hospitals’ (N = 92) quality improvement (QI) leaders was conducted among HQID hospitals in the top 2 or bottom 2 deciles submitting performance measure data from October 2004 to September 2005. The survey covered topics such as QI interventions, data feedback, physician leadership, support for QI efforts, and organizational culture.RESULTSMore top performing hospitals used clinical pathways for the treatment of AMI (49% vs. 15%, p < 0.01), HF (44% vs. 18%, p < 0.01), PN (38% vs. 13%, p < 0.01) and THR/TKR (56% vs. 23%, p < 0.01); organized into multidisciplinary teams to manage patients with AMI (93% vs. 77%, p < 0.05) and HF (93% vs. 69%, p < 0.01); used order sets for the treatment of THR/TKR (91% vs. 64%, p < 0.01); and implemented computerized physician order entry in the hospital (24.4% vs. 7.9%, p < 0.05). Finally, more top performers reported having adequate human resources for QI projects (p < 0.01); support of the nursing staff to increase adherence to quality indicators (p < 0.01); and an organizational culture that supported coordination of care (p < 0.01), pace of change (p < 0.01), willingness to try new projects (p < 0.01), and a focus on identifying system errors rather than blaming individuals (p < 0.05).CONCLUSIONSOrganizational structure, support, and culture are associated with high performance among hospitals participating in a pay-for-performance demonstration project. Multiple organizational factors remain important in optimizing clinical care.

Cost analysis of switching from IV vancomycin to PO linezolid for the management of methicillin-resistant Staphylococcus species

BACKGROUND Infections with methicillin-resistant Staphylococcus species (MRSS) are associated with higher treatment costs than infections with methicillin-sensitive Staphylococcus species in the United States--partly because of an increased length of hospital stay (LOS). OBJECTIVE This study used pharmacoeconomic modeling to evaluate the costs and outcomes associated with the use of i.v. vancomycin compared with p.o. linezolid in the treatment of MRSS-infected patients. METHODS A retrospective chart review was used to determine the number of cases with confirmed or presumed MRSS infections treated with i.v. vancomycin during calendar-year 2000 at the Veterans Affairs Greater Los Angeles Healthcare System inpatient facility. Patients who were eligible for a switch to p.o. linezolid with or without early discharge to home were identified. Cost differences associated with conversion from i.v. to p.o. therapy (compared with continued i.v. therapy) were estimated based on a mean decreased LOS and a decrease in the costs associated with catheter-related adverse events. Rates and costs of catheter-related adverse events were based on estimates from the literature. Sensitivity analyses were performed by variation of the estimated mean LOS decrease in the SD and by variation of the estimates for incidence and costs related to catheter complications. Costs were measured in year 2000 US dollars, and differences were not assessed for statistical significance. RESULTS Of 177 patients treated with i.v. vancomycin, 103 (58%) were eligible for conversion to p.o. linezolid and 55 (31%) were eligible for early discharge from the hospital with continuation of p.o. therapy. Early discharge was associated with a mean (SD) LOS decrease of 3.3 (2.9) days. Annual mean total cost savings in patients eligible for conversion from i.v. vancomycin to p.o. linezolid with early discharge were

Achieving a safe and early discharge for patients with community-acquired pneumonia.

294,750 (range,

Prevention of a First Stroke A Review of Guidelines and a Multidisciplinary Consensus Statement From the National Stroke Association

35,730-

Early Switch and Early Discharge Strategies in Patients With Community-Acquired Pneumonia: A Meta-analysis

553,790). For cases eligible for inpatient conversion from i.v. vancomycin to p.o. linezolid therapy (n=48), the mean total annual cost difference was an increase of

A Prospective, Multicenter Study of a Pneumonia Practice Guideline

6340 for p.o. linezolid (range, -

The Clinical Benefit of In-Hospital Observation in ‘Low-risk’ Pneumonia Patients After Conversion From Parenteral to Oral Antimicrobial Therapy

12,910 to