Testing for pulmonary embolism often differs from that recommended by evidence-based guidelines.
To assess the effectiveness of a handheld clinical decision-support system to improve the diagnostic work-up of suspected pulmonary embolism among patients in the emergency department.
Cluster randomized trial. Assignment was by random-number table, providers were not blinded, and outcome assessment was automated. (ClinicalTrials.gov registration number: NCT00188032)
20 emergency departments in France.
1103 and 1768 consecutive outpatients with suspected pulmonary embolism.
After a preintervention period involving 20 centers and 1103 patients, in which providers grew accustomed to inputting clinical data into handheld devices and investigators assessed baseline testing, emergency departments were randomly assigned to activation of a decision-support system on the devices (10 centers, 753 patients) or posters and pocket cards that showed validated diagnostic strategies (10 centers, 1015 patients).
Appropriateness of diagnostic work-up, defined as any sequence of tests that yielded a posttest probability less than 5% or greater than 85% (primary outcome) or as strict adherence to guideline recommendations (secondary outcome); number of tests per patient (secondary outcome).
The proportion of patients who received appropriate diagnostic work-ups was greater during the trial than in the preintervention period in both groups, but the increase was greater in the computer-based guidelines group (adjusted mean difference in increase, 19.3 percentage points favoring computer-based guidelines [95% CI, 2.9 to 35.6 percentage points]; P = 0.023). Among patients with appropriate work-ups, those in the computer-based guidelines group received slightly fewer tests than did patients in the paper guidelines group (mean tests per patient, 1.76 [SD, 0.98] vs. 2.25 [SD, 1.04]; P < 0.001).
The study was not designed to show a difference in the clinical outcomes of patients during follow-up.
A handheld decision-support system improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.
French National Hospital Clinical Research Project.
Fewer than 40% of persons with hypertension in the United States have adequate blood pressure (BP) control.
To compare 2 self-management interventions for improving BP control among hypertensive patients.
A 2 x 2 randomized trial, stratified by enrollment site and patient health literacy status, with 2-year follow-up. (ClinicalTrials.gov registration number: NCT00123058)
2 university-affiliated primary care clinics.
636 hypertensive patients.
A centralized, blinded, and stratified randomization algorithm was used to randomly assign eligible patients to receive usual care, a behavioral intervention (bimonthly tailored, nurse-administered telephone intervention targeting hypertension-related behaviors), home BP monitoring 3 times weekly, or the behavioral intervention plus home BP monitoring.
The primary outcome was BP control at 6-month intervals over 24 months.
475 patients (75%) completed the 24-month BP follow-up. At 24 months, improvements in the proportion of patients with BP control relative to the usual care group were 4.3% (95% CI, –4.5% to 12.9%) in the behavioral intervention group, 7.6% (CI, –1.9% to 17.0%) in the home BP monitoring group, and 11.0% (CI, 1.9%, 19.8%) in the combined intervention group. Relative to usual care, the 24-month difference in systolic BP was 0.6 mm Hg (CI, –2.2 to 3.4 mm Hg) for the behavioral intervention group, –0.6 mm Hg (CI, –3.6 to 2.3 mm Hg) for the BP monitoring group, and –3.9 mm Hg (CI, –6.9 to –0.9 mm Hg) for the combined intervention group; patterns were similar for diastolic BP.
Changes in medication use and diet were monitored only in intervention participants; 24-month outcome data were missing for 25% of participants, BP control was adequate at baseline in 73% of participants, and the study setting was an academic health center.
Combined home BP monitoring and tailored behavioral telephone intervention improved BP control, systolic BP, and diastolic BP at 24 months relative to usual care.
National Heart, Lung, and Blood Institute; Pfizer Foundation Health Communication Initiative; and the American Heart Association.
Adherence to short-term continuous positive airway pressure (CPAP) may predict long-term use. Unfortunately, initial CPAP intolerance may lead to poor adherence or abandonment of therapy.
To determine whether a short course of eszopiclone at the onset of therapy improves long-term CPAP adherence more than placebo in adults with obstructive sleep apnea.
Parallel randomized, placebo-controlled trial from March 2007 to December 2008. Randomization, maintained and concealed centrally by pharmacy personnel, was computer-generated using fixed blocks of 10. Referring physicians, investigators, and patients were blinded to the treatment assignment until after the final data were collected. (ClinicalTrials.gov registration number: NCT00612157)
Academic sleep disorder center.
160 adults (mean age, 45.7 years [SD, 7.3]; mean apnea–hypopnea index, 36.9 events/h [SD, 23]) with newly diagnosed obstructive sleep apnea initiating CPAP.
Eszopiclone, 3 mg (n = 76), or matching placebo (n = 78) for the first 14 nights of CPAP.
Use of CPAP was measured weekly for 24 weeks. Adherence to CPAP (primary outcome) and the rate of CPAP discontinuation and improvements in symptoms (secondary outcomes) were compared. Follow-up at 1, 3, and 6 months was completed by 150, 136, and 120 patients, respectively.
Patients in the eszopiclone group used CPAP for 20.8% more nights (95% CI, 7.2% to 34.4%; P = 0.003), 1.3 more hours per night for all nights (CI, 0.4 to 2.2 hours; P = 0.005), and 1.1 more hours per night of CPAP use (CI, 0.2 to 2.1 hours; P = 0.019). The hazard ratio for discontinuation of CPAP was 1.90 (CI, 1.1 to 3.4; P = 0.033) times higher in the placebo group. Side effects were reported in 7.1% of patients and did not differ between groups.
Patients had severe obstructive sleep apnea treated at a specialized sleep center with frequent follow-up; results may not be generalizable to different settings. Patients' tolerance to CPAP and their reasons for discontinuation were not assessed.
Compared with placebo, a short course of eszopiclone during the first 2 weeks of CPAP improved adherence and led to fewer patients discontinuing therapy.
Sepracor.
Trials demonstrate the efficacy of medications to reduce the risk for invasive breast cancer.
To summarize benefits and harms of tamoxifen citrate, raloxifene, and tibolone to reduce the risk for primary breast cancer.
MEDLINE and Cochrane databases from inception to January 2009, Web of Science, trial registries, and manufacturer information.
Predefined eligibility criteria were used to select articles. English-language reports of randomized, controlled trials (RCTs) for benefits and RCTs and observational studies for harms were included.
Two reviewers assessed study data, quality, and applicability.
Seven placebo-controlled RCTs and 1 head-to-head trial provide results for main outcomes. Tamoxifen (risk ratio, 0.70 [95% CI, 0.59 to 0.82]; 4 trials), raloxifene (risk ratio, 0.44 [CI, 0.27 to 0.71]; 2 trials), and tibolone (risk ratio, 0.32 [CI, 0.13 to 0.80]; 1 trial) reduce risk for invasive breast cancer compared with placebo by 7 to 10 per 1000 women per year. Tamoxifen and raloxifene reduce estrogen receptor–positive breast cancer but not estrogen receptor–negative breast cancer, noninvasive breast cancer, or mortality. All medications reduce fractures. Tamoxifen (risk ratio, 1.93 [CI, 1.41 to 2.64]; 4 trials) and raloxifene (risk ratio, 1.60 [CI, 1.15 to 2.23]; 2 trials) increase thromboembolic events by 4 to 7 per 1000 women per year; raloxifene causes fewer events than tamoxifen. Tamoxifen increases risk for endometrial cancer (risk ratio, 2.13 [CI, 1.36 to 3.32]; 3 trials) compared with placebo by 4 per 1000 women per year and causes cataracts compared with raloxifene. Tibolone causes strokes in older women.
Bias, trial heterogeneity, and a dearth of head-to-head trials limit this review. Data are lacking on doses, duration, and timing of the medications; long-term effects; and nonwhite and premenopausal women.
Three medications reduce risk for primary breast cancer but increase risk for thromboembolic events (tamoxifen, raloxifene), endometrial cancer (tamoxifen), or stroke (tibolone).
Agency for Healthcare Research and Quality.
Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for breast cancer in the general population.
The USPSTF examined the evidence on the efficacy of 5 screening modalities in reducing mortality from breast cancer: film mammography, clinical breast examination, breast self-examination, digital mammography, and magnetic resonance imaging in order to update the 2002 recommendation. To accomplish this update, the USPSTF commissioned 2 studies: 1) a targeted systematic evidence review of 6 selected questions relating to benefits and harms of screening, and 2) a decision analysis that used population modeling techniques to compare the expected health outcomes and resource requirements of starting and ending mammography screening at different ages and using annual versus biennial screening intervals.
The USPSTF recommends against routine screening mammography in women aged 40 to 49 years. The decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient's values regarding specific benefits and harms. (Grade C recommendation)
The USPSTF recommends biennial screening mammography for women between the ages of 50 and 74 years. (Grade B recommendation)
The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of screening mammography in women 75 years or older. (I statement)
The USPSTF concludes that the current evidence is insufficient to assess the additional benefits and harms of clinical breast examination beyond screening mammography in women 40 years or older. (I statement)
The USPSTF recommends against clinicians teaching women how to perform breast self-examination. (Grade D recommendation)
The USPSTF concludes that the current evidence is insufficient to assess additional benefits and harms of either digital mammography or magnetic resonance imaging instead of film mammography as screening modalities for breast cancer. (I statement)
This systematic review is an update of evidence since the 2002 U.S. Preventive Services Task Force recommendation on breast cancer screening.
To determine the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women aged 40 to 49 years and 70 years or older, the effectiveness of clinical breast examination and breast self-examination, and the harms of screening.
Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2008), MEDLINE (January 2001 to December 2008), reference lists, and Web of Science searches for published studies and Breast Cancer Surveillance Consortium for screening mammography data.
Randomized, controlled trials with breast cancer mortality outcomes for screening effectiveness, and studies of various designs and multiple data sources for harms.
Relevant data were abstracted, and study quality was rated by using established criteria.
Mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years (relative risk, 0.85 [95% credible interval, 0.75 to 0.96]; 8 trials). Data are lacking for women aged 70 years or older. Radiation exposure from mammography is low. Patient adverse experiences are common and transient and do not affect screening practices. Estimates of overdiagnosis vary from 1% to 10%. Younger women have more false-positive mammography results and additional imaging but fewer biopsies than older women. Trials of clinical breast examination are ongoing; trials for breast self-examination showed no reductions in mortality but increases in benign biopsy results.
Studies of older women, digital mammography, and magnetic resonance imaging are lacking.
Mammography screening reduces breast cancer mortality for women aged 39 to 69 years; data are insufficient for older women. False-positive mammography results and additional imaging are common. No benefit has been shown for clinical breast examination or breast self-examination.
Agency for Healthcare Research and Quality.
Despite trials of mammography and widespread use, optimal screening policy is controversial.
To evaluate U.S. breast cancer screening strategies.
6 models using common data elements.
National data on age-specific incidence, competing mortality, mammography characteristics, and treatment effects.
A contemporary population cohort.
Lifetime.
Societal.
20 screening strategies with varying initiation and cessation ages applied annually or biennially.
Number of mammograms, reduction in deaths from breast cancer or life-years gained (vs. no screening), false-positive results, unnecessary biopsies, and overdiagnosis.
The 6 models produced consistent rankings of screening strategies. Screening biennially maintained an average of 81% (range across strategies and models, 67% to 99%) of the benefit of annual screening with almost half the number of false-positive results. Screening biennially from ages 50 to 69 years achieved a median 16.5% (range, 15% to 23%) reduction in breast cancer deaths versus no screening. Initiating biennial screening at age 40 years (vs. 50 years) reduced mortality by an additional 3% (range, 1% to 6%), consumed more resources, and yielded more false-positive results. Biennial screening after age 69 years yielded some additional mortality reduction in all models, but overdiagnosis increased most substantially at older ages.
Varying test sensitivity or treatment patterns did not change conclusions.
Results do not include morbidity from false-positive results, patient knowledge of earlier diagnosis, or unnecessary treatment.
Biennial screening achieves most of the benefit of annual screening with less harm. Decisions about the best strategy depend on program and individual objectives and the weight placed on benefits, harms, and resource considerations.
National Cancer Institute.
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Despite convincing evidence that lowering blood pressure decreases cardiovascular morbidity and mortality, the hypertension burden remains high and control rates are poor in developing countries.
To assess the effectiveness of 2 community-based interventions on blood pressure in hypertensive adults.
Cluster randomized, 2 x 2 factorial, controlled trial. (ClinicalTrials.gov registration number: NCT00327574)
12 randomly selected communities in Karachi, Pakistan.
1341 patients 40 years or older with hypertension (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or already receiving treatment).
Reduction in systolic blood pressure from baseline to end of follow-up at 2 years.
Family-based home health education (HHE) from lay health workers every 3 months and annual training of general practitioners (GPs) in hypertension management.
The age, sex, and baseline blood pressure–adjusted decrease in systolic blood pressure was significantly greater in the HHE and GP group (10.8 mm Hg [95% CI, 8.9 to 12.8 mm Hg]) than in the GP-only, HHE-only, or no intervention groups (5.8 mm Hg [CI, 3.9 to 7.7 mm Hg] in each; P < 0.001). The interaction between the main effects of GP training and HHE on the primary outcome approached significance (interaction P = 0.004 in intention-to-treat analysis and P = 0.044 in per-protocol analysis).
Follow-up blood pressure measurements were missing for 22% of patients. No mechanism was detected by which interventions lowered blood pressure.
Family-based HHE delivered by trained lay health workers, coupled with educating GPs on hypertension, can lead to significant blood pressure reductions among patients with hypertension in Pakistan. Both strategies in combination may be feasible for upscaling within the existing health care systems of Indo-Asian countries.
Wellcome Trust.
Cervical cancer screening guidelines were substantially revised in 2002 and 2003. Little information is available about primary care physicians' current Papanicolaou (Pap) test screening practices, including initiation, frequency, and stopping.
To assess current Pap test screening practices in the United States.
Cross-sectional survey.
Nationally representative sample of physicians during 2006 to 2007.
1212 primary care physicians.
The survey included questions about physician and practice characteristics and recommendations for Pap screening presented as clinical vignettes describing women by age and by sexual and screening histories. A composite measure—guideline-consistent recommendations—was created by using responses to vignettes in which major guidelines were uniform.
Most physicians reported providing Pap tests to their eligible patients (91.0% [95% CI, 89.0% to 92.6%]). Among Pap test providers (n = 1114), screening practices, including number of tests ordered or performed, use of patient reminder systems, and cytology method used, varied by physician specialty (P < 0.001). Although most Pap test providers reported that screening guidelines were very influential in their clinical practice, few had guideline-consistent recommendations for starting and stopping Pap screening across multiple vignettes (22.3% [CI, 19.9% to 25.0%]). Guideline-consistent recommendations varied by specialty (obstetrics/gynecology, 16.4%; internal medicine, 27.5%; and family or general practice, 21.1%). Compared with obstetricians/gynecologists, internal medicine specialists and family or general practice specialists were more likely to have guideline-consistent screening recommendations (odds ratio, 1.98 [CI, 1.22 to 3.23] and 1.45 [CI, 0.99 to 2.13], respectively) in multivariate analysis.
Physician self-report may reflect idealized rather than actual practice.
Primary care physicians' recommendations for Pap test screening are not consistent with screening guidelines, reflecting overuse of screening. Implementation of effective interventions that focus on potentially modifiable physician and practice factors is needed to improve screening practice.
National Cancer Institute, Centers for Disease Control and Prevention, and Agency for Healthcare Research and Quality.
Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined.
To assess the potential cost-effectiveness of major therapeutic strategies for very early RA.
Decision analytic model with probabilistic sensitivity analyses.
Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs.
U.S. adults with very early RA (symptom duration ≤3 months).
Lifetime.
Health care provider and societal.
3 management strategies were compared: a symptomatic or "pyramid" strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate.
Cost per quality-adjusted life-year (QALY) gained.
By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.
The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed.
Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics.
According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.
Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved.
To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease.
English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008).
A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or -3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes.
Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach.
102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin–ezetimibe (2 trials; n = 439) and statin–fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin–ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality.
Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin–ezetimibe.
Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin–ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals.
Agency for Healthcare Research and Quality.
Intravenous sodium bicarbonate has been proposed to reduce the risk for contrast-induced nephropathy (CIN).
To determine the effect of sodium bicarbonate on the risk for CIN.
MEDLINE, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials from 1950 to December 2008; conference proceedings; and ClinicalTrials.gov, without language restriction.
Randomized, controlled trials of intravenous sodium bicarbonate that prespecified the outcome of CIN as a 25% increase in baseline serum creatinine level or an absolute increase of 44 µmol/L (0.5 mg/dL) after radiocontrast administration.
Using standardized protocols, 2 reviewers serially abstracted data for each study.
23 published and unpublished trials with information on 3563 patients and 396 CIN events were included. The pooled relative risk was 0.62 (95% CI, 0.45 to 0.86), with evidence of significant heterogeneity across studies (I 2 = 49.1%; P = 0.004). Some heterogeneity was due to the difference in the estimates between published and unpublished studies: relative risk, 0.43 (CI, 0.25 to 0.75) versus 0.78 (CI, 0.52 to 1.17), respectively. Meta-regression showed that small, poor-quality studies that assessed outcomes soon after radiocontrast administration were more likely to suggest benefit (P < 0.05 for all). No clear effects of treatment on the risk for dialysis, heart failure, and total mortality were identified.
Power to assess clinical end points was limited.
The effectiveness of sodium bicarbonate treatment to prevent CIN in high-risk patients remains uncertain. Earlier reports probably overestimated the magnitude of any benefit, whereas larger, more recent trials have had neutral results. Large multicenter trials are required to clarify whether sodium bicarbonate has value for prevention of CIN before routine use can be recommended.
None.
The American College of Physicians developed this guideline to present the available evidence on hormonal testing in and pharmacologic management of erectile dysfunction. Current pharmacologic therapies include phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, vardenafil, tadalafil, mirodenafil, and udenafil, and hormonal treatment.
Published literature on this topic was identified by using MEDLINE (1966 to May 2007), EMBASE (1980 to week 22 of 2007), Cochrane Central Register of Controlled Trials (second quarter of 2007), PsycINFO (1985 to June 2007), AMED (1985 to June 2007), and SCOPUS (2006). The literature search was updated by searching for articles in MEDLINE and EMBASE published between May 2007 and April 2009. Searches were limited to English-language publications. This guideline grades the evidence and recommendations by using the American College of Physicians' clinical practice guidelines grading system.
The American College of Physicians recommends that clinicians initiate therapy with a PDE-5 inhibitor in men who seek treatment for erectile dysfunction and who do not have a contraindication to PDE-5 inhibitor use (Grade: strong recommendation; high-quality evidence).
The American College of Physicians recommends that clinicians base the choice of a specific PDE-5 inhibitor on the individual preferences of men with erectile dysfunction, including ease of use, cost of medication, and adverse effects profile (Grade: weak recommendation; low-quality evidence).
The American College of Physicians does not recommend for or against routine use of hormonal blood tests or hormonal treatment in the management of patients with erectile dysfunction (Grade: insufficient evidence to determine net benefits and harms).
Erectile dysfunction (ED) is a common male sexual disorder. The relative benefits and harms of pharmacologic therapies for ED, as well as the value of hormonal testing in men with ED, are uncertain.
To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for ED and assess the effect of measuring serum hormone levels on treatment outcomes for ED.
English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS through April 2009. Trial reference lists also were scanned.
Randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED.
Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities.
Data, primarily from short-term trials (≤12 weeks), indicate that PDE-5 inhibitors were more effective than placebo in improving sexual intercourse success (69.0% vs. 35.0%). The proportion of men with improved erections was significantly greater among those treated with PDE-5 inhibitors (range, 67.0% to 89.0%) than with placebo (range, 27.0% to 35.0%). The PDE-5 inhibitors were associated with increased risk for any adverse events compared with placebo (for example, relative risk with sildenafil, 1.72 [95% CI, 1.53 to 1.93]). In 4 head-to-head RCTs comparing sildenafil, vardenafil, and tadalafil, improvement of ED and adverse events did not differ among treatments. Results from 15 RCTs evaluating hormonal treatment of ED were inconsistent on whether treatment improved outcomes. Evidence was insufficient regarding whether men with ED had a higher prevalence of hypogonadism than men without ED.
Many RCTs were of low methodological and reporting quality, particularly those involving hormonal treatments or directly comparing different PDE-5 inhibitors. Most RCTs provided only short-term efficacy and harms data.
Oral PDE-5 inhibitors improved erectile functioning and had similar efficacy and safety profiles. Results on the efficacy of hormonal treatments and the value of hormone testing in men with ED were inconclusive.
Agency for Healthcare Research and Quality.
Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD.
Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847)
Setting: 2 university medical centers in The Netherlands.
Patients: 114 steroid-naive current or former smokers with moderate to severe COPD.
Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months.
Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 µg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29).
Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (–55% [95% CI, –74% to –22%]; P = 0.004), CD4+ cells (–78% [CI, –88% to 60%]; P < 0.001), CD8+ cells (–57% [CI, –77% to –18%]; P = 0.010), and mast cells (–38% [CI, –60% to –2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level.
Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months.
Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects.
Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.
]]>Objective: To assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.
Design: Large-scale meta-analysis of genome-wide association data.
Setting: 5 international, multicenter, population-based studies.
Participants: Data on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.
Measurements: Systematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.
Results: 150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.
Limitation: Only common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.
Conclusion: In this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.
Primary Funding Source: European Union, Netherlands Organisation for Scientific Research, Research Institute for Diseases in the Elderly, Netherlands Genomics Initiative, Wellcome Trust, National Institutes of Health, deCODE Genetics, and Canadian Institutes of Health Research.
]]>Objective: To assess the health and economic outcomes of HPV vaccination in older U.S. women.
Design: Cost-effectiveness analysis with an empirically calibrated model.
Data Sources: Published literature.
Target Population: U.S. women aged 35 to 45 years.
Time Horizon: Lifetime.
Perspective: Societal.
Intervention: HPV vaccination added to screening strategies that differ by test (cytology or HPV DNA testing), frequency, and start age versus screening alone.
Outcome Measures: Incremental cost-effectiveness ratios (2006 U.S. dollars per quality-adjusted life-year [QALY] gained).
Results of Base-Case Analysis: In the context of annual or biennial screening, HPV vaccination of women aged 35 to 45 years ranged from $116 950 to $272 350 per QALY for cytology with HPV DNA testing for triage of equivocal results and from $193 690 to $381 590 per QALY for combined cytology and HPV DNA testing, depending on age and screening frequency.
Results of Sensitivity Analysis: The probability of HPV vaccination being cost-effective for women aged 35 to 45 years was 0% with annual or biennial screening and less than 5% with triennial screening, at thresholds considered good value for money.
Limitation: The natural history of the disease and the efficacy of the vaccine in older women are uncertain.
Conclusion: Given currently available information, the effectiveness of HPV vaccination for women older than 30 years who are screened seems to be small. Compared with current screening that uses sensitive HPV DNA testing, HPV vaccination is associated with less attractive cost-effectiveness ratios in this population than those for other, well-accepted interventions in the United States.
Primary Funding Source: National Cancer Institute, Centers for Disease Control and Prevention, and the American Cancer Society.
]]>Objective: To assess the magnitude and duration of risk for hospital contact with infection associated with splenectomy.
Design: Population-based cohort study.
Setting: Denmark.
Patients: All 3812 persons in Denmark who underwent splenectomy from 1996 to 2005. Splenectomized patients were matched to 3 comparison cohorts: the general population, appendectomized patients, and unsplenectomized patients with indications for splenectomy.
Measurements: Relative risks were assessed for hospital contact involving any infection, pneumonia, and microbiologically confirmed bacteremia among 3812 splenectomized patients and their matched comparisons, during different follow-up periods and after regression analysis for confounder adjustment.
Results: The adjusted relative risk for any hospital contact with infection was highest within 90 days of splenectomy: 10.2% vs. 0.6% among general population comparisons (adjusted odds ratio, 18.1 [95% CI, 14.8 to 22.1]) and 10.2% vs. 4.2% among appendectomized patients (adjusted odds ratio, 2.4 [CI, 2.1 to 2.8]). The hazard of infection was 4.6-fold (CI, 3.8 to 5.5) higher in splenectomized patients than in general population comparisons from 91 to 365 days after splenectomy and 2.5 times (CI, 2.2 to 2.8) higher more than 365 days after splenectomy. The risks were similar for pneumonia and were higher for bacteremia. Markedly increased risks were also found when compared with those of appendectomized patients. Modest increases in infection risk were seen with splenectomy matched-indication comparisons (adjusted 90-day odds ratio, 1.7 [CI, 1.5 to 2.1]; hazard ratios, 1.5 [CI, 1.2 to 1.8] from 91 to 365 days after splenectomy and 1.2 [CI, 1.1 to 1.4] beyond 365 days after splenectomy). Relative risks for infection were highest in patients who had splenectomy because of hematologic disorders.
Limitation: Increased surveillance among splenectomized patients may have affected the findings.
Conclusion: Splenectomy is associated with increased long-term risk for infections involving hospital contact.
Primary Funding Source: Amgen, Clinical Epidemiological Research Foundation at Aarhus University, and Karen Elise Jensen Foundation.
]]>Purpose: To review evidence about the benefits and harms of charged-particle radiation therapy for patients with cancer.
Data Sources: MEDLINE (inception to 11 July 2009) was searched for publications in English, German, French, Italian, and Japanese. Web sites of manufacturers, treatment centers, and professional organizations were searched for relevant information.
Study Selection: Four reviewers identified studies of any design that described clinical outcomes or adverse events in 10 or more patients with cancer treated with charged-particle radiation therapy.
Data Extraction: The 4 reviewers extracted study, patient, and treatment characteristics; clinical outcomes; and adverse events for nonoverlapping sets of articles. A fifth reviewer verified data on comparative studies.
Data Synthesis: Currently, 7 centers in the United States have facilities for particle (proton)–beam irradiation, and at least 4 are under construction, each costing between $100 and $225 million. In 243 eligible articles, charged-particle radiation therapy was used alone or in combination with other interventions for common (for example, lung, prostate, or breast) or uncommon (for example, skull-base tumors or uveal melanomas) types of cancer. Of 243 articles, 185 were single-group retrospective studies. Eight randomized and 9 nonrandomized clinical trials compared treatments with or without charged particles. No comparative study reported statistically significant or important differences in overall or cancer-specific survival or in total serious adverse events.
Limitation: Few studies directly compared treatments with or without particle irradiation.
Conclusion: Evidence on the comparative effectiveness and safety of charged-particle radiation therapy in cancer is needed to assess the benefits, risks, and costs of treatment alternatives.
Primary Funding Source: Agency for Healthcare Research and Quality.
]]>Purpose: To determine whether ventilation with low tidal volume (V
Data Sources: Multiple computerized databases (through March 2009), reference lists of identified articles, and queries of principal investigators. No language restrictions were applied.
Study Selection: Randomized, controlled trials (RCTs) reporting mortality and comparing lower versus higher V
Data Extraction: Using a standard protocol, 2 reviewer teams assessed trial eligibility and abstracted data on quality of study design and conduct, population characteristics, intervention, co-interventions, and confounding variables.
Data Synthesis: 4 RCTs tested lower versus higher V
Limitations: Pooling according to similar ventilatory strategies resulted in few RCTs analyzed in each group. The benefit of low V
Conclusion: Available evidence from a limited number of RCTs shows better outcomes with routine use of low V
Primary Funding Source: None.
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Objective: To investigate whether hand hygiene and use of facemasks prevents household transmission of influenza.
Design: Cluster randomized, controlled trial. Randomization was computer generated; allocation was concealed from treating physicians and clinics and implemented by study nurses at the time of the initial household visit. Participants and personnel administering the interventions were not blinded to group assignment. (ClinicalTrials.gov registration number: NCT00425893)
Setting: Households in Hong Kong.
Patients: 407 people presenting to outpatient clinics with influenza-like illness who were positive for influenza A or B virus by rapid testing (index patients) and 794 household members (contacts) in 259 households.
Intervention: Lifestyle education (control) (134 households), hand hygiene (136 households), or surgical facemasks plus hand hygiene (137 households) for all household members.
Measurements: Influenza virus infection in contacts, as confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or diagnosed clinically after 7 days.
Results: Sixty (8%) contacts in the 259 households had RT-PCR–confirmed influenza virus infection in the 7 days after intervention. Hand hygiene with or without facemasks seemed to reduce influenza transmission, but the differences compared with the control group were not significant. In 154 households in which interventions were implemented within 36 hours of symptom onset in the index patient, transmission of RT-PCR–confirmed infection seemed reduced, an effect attributable to fewer infections among participants using facemasks plus hand hygiene (adjusted odds ratio, 0.33 [95% CI, 0.13 to 0.87]). Adherence to interventions varied.
Limitation: The delay from index patient symptom onset to intervention and variable adherence may have mitigated intervention effectiveness.
Conclusion: Hand hygiene and facemasks seemed to prevent household transmission of influenza virus when implemented within 36 hours of index patient symptom onset. These findings suggest that nonpharmaceutical interventions are important for mitigation of pandemic and interpandemic influenza.
Primary Funding Source: Centers for Disease Control and Prevention.
]]>Objective: To compare the effects of sleep restriction and alcohol on driving simulator performance in patients with OSA and age-matched control participants.
Design: Driving simulator assessments in 2 groups under 3 different conditions presented in random order.
Setting: Adelaide Institute for Sleep Health, Sleep Laboratory, Adelaide, Australia.
Participants: 38 untreated patients with OSA and 20 control participants.
Measurements: Steering deviation, crashes, and braking reaction time.
Intervention: Unrestricted sleep, sleep restricted to a maximum of 4 hours, and ingestion of an amount of 40% vodka calculated to achieve a blood alcohol level of 0.05 g/dL.
Results: Patients with OSA demonstrated increased steering deviation compared with control participants (mean, 50.5 cm [95% CI, 46.1 to 54.9 cm] in the OSA group and 38.4 cm [CI, 32.4 to 44.4 cm] in the control group; P < 0.01) and significantly greater steering deterioration over time (group by time interaction, P = 0.02). The increase in steering deviation after sleep restriction and alcohol was approximately 40% greater in patients with OSA than in control participants (group by condition interaction, P = 0.04). Patients with OSA crashed more frequently than control participants (1 vs. 24 participants; odds ratio [OR], 25.4; P = 0.03) and crashed more frequently after sleep restriction (OR, 4.0; P < 0.01) and alcohol consumption (OR, 2.3; P = 0.02) than after normal sleep. In patients with OSA, prolonged eye closure (>2 seconds) and microsleeps (> 2 seconds of theta activity on electroencephalography) were significant crash predictors (OR, 19.2 and 7.2, respectively; P < 0.01). Braking reaction time was slower after sleep restriction than after normal sleep (mean, 1.39 [SD, 0.06] seconds vs. 1.22 [SD, 0.04] seconds; P < 0.01) but not after alcohol consumption. No group differences were found.
Limitation: Simulated driving was assessed rather than on-road driving.
Conclusion: Patients with OSA are more vulnerable than healthy persons to the effects of alcohol consumption and sleep restriction on various driving performance variables.
Primary Funding Source: Australian National Health and Medical Research Council.
]]>Objective: To measure associations between structural capabilities of primary care practices and performance on commonly used quality measures.
Design: Cross-sectional analysis.
Setting: Massachusetts.
Participants: 412 primary care practices.
Measurements: During 2007, 1 physician from each participating primary care practice (median size, 4 physicians) was surveyed about structural capabilities of the practice (responses representing 308 practices were obtained). Data on practice structural capabilities were linked to multipayer performance data on 13 Healthcare Effectiveness Data and Information Set (HEDIS) process measures in 4 clinical areas: screening, diabetes, depression, and overuse.
Results: Frequently used multifunctional electronic health records were associated with higher performance on 5 HEDIS measures (3 in screening and 2 in diabetes), with statistically significant differences in performance ranging from 3.1 to 7.6 percentage points. Frequent meetings to discuss quality were associated with higher performance on 3 measures of diabetes care (differences ranging from 2.3 to 3.1 percentage points). Physician awareness of patient experience ratings was associated with higher performance on screening for breast cancer and cervical cancer (1.9 and 2.2 percentage points, respectively). No other structural capabilities were associated with performance on more than 1 measure. No capabilities were associated with performance on depression care or overuse.
Limitation: Structural capabilities of primary care practices were assessed by physician survey.
Conclusion: Among the investigated structural capabilities of primary care practices, electronic health records were associated with higher performance across multiple HEDIS measures. Overall, the modest magnitude and limited number of associations between structural capabilities and clinical performance suggest the importance of continuing to measure the processes and outcomes of care for patients.
Primary Funding Source: The Commonwealth Fund.
]]>Purpose: To evaluate the safety and efficacy of extended-duration (>4 weeks) NAI chemoprophylaxis against influenza.
Data Sources: Studies published in any language through 11 June 2009 identified by searching 10 electronic databases and 3 trial registries.
Study Selection: Randomized, placebo-controlled, double-blind human trials of extended-duration NAI chemoprophylaxis that reported outcomes of laboratory-confirmed influenza or adverse events.
Data Extraction: 2 reviewers independently assessed study quality and abstracted information from eligible studies.
Data Synthesis: Of 1876 potentially relevant citations, 7 trials involving 7021 unique participants met inclusion criteria. Data were pooled by using random-effects models. Chemoprophylaxis with NAIs decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], –3.9 percentage points [CI, –5.8 to –1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, –0.4 percentage point [CI, –1.6 to 0.9 percentage point]). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, –0.2 to 0.4 percentage point]), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir.
Limitations: All trials were industry-sponsored. No study was powered to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine.
Conclusion: Extended-duration zanamivir and oseltamivir chemoprophylaxis seems to be highly efficacious for preventing symptomatic influenza among immunocompetent white and Japanese adults. Extended-duration oseltamivir is associated with increased nausea and vomiting. Safety and efficacy in several subpopulations that might receive extended-duration influenza chemoprophylaxis are unknown.
]]>Methods: Systematic reviews were conducted of literature since 1996 on 9 proposed nontraditional markers of CHD risk: high-sensitivity C-reactive protein, ankle–brachial index, leukocyte count, fasting blood glucose, periodontal disease, carotid intima–media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine, and lipoprotein(a). The reviews followed a hierarchical approach aimed at determining which factors could practically and definitively reassign persons assessed as intermediate-risk according to their Framingham score to either a high-risk or low-risk strata, and thereby improve outcomes by means of aggressive risk-factor modification in those newly assigned to the high-risk stratum.
Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors studied to screen asymptomatic men and women with no history of CHD to prevent CHD events. (I statement).
]]>Purpose: To assist the U.S. Preventive Services Task Force (USPSTF) in determining whether CRP should be incorporated into guidelines for CHD risk assessment.
Data Sources: MEDLINE search of English-language articles (1966 to November 2007), supplemented by reference lists of reviews, pertinent studies, editorials, and Web sites and by expert suggestions.
Study Selection: Prospective cohort, case–cohort, and nested case–control studies relevant to the independent predictive ability of CRP when used in intermediate-risk persons.
Data Extraction: Included studies were reviewed according to predefined criteria, and the quality of each study was rated.
Data Synthesis: The validity of the body of evidence and the net benefit or harm of using CRP for CHD risk assessment were evaluated. The combined magnitude of effect was determined by meta-analysis. The body of evidence is of good quality, consistency, and applicability. For good studies that adjusted for all Framingham risk variables, the summary estimate of relative risk for incident CHD was 1.58 (95% CI, 1.37 to 1.83) for CRP levels greater than 3.0 mg/L compared with levels less than 1.0 mg/L. Analyses from 4 large cohorts were consistent in finding evidence that including CRP improves risk stratification among initially intermediate-risk persons. C-reactive protein has desirable test characteristics, and good data exist on the prevalence of elevated CRP levels in intermediate-risk persons. Limited evidence links changes in CRP level to primary prevention of CHD events.
Limitations: Study methods for measuring Framingham risk variables and other covariates varied. Ethnic and racial minority populations were poorly represented in most studies, limiting generalizability. Few studies directly assessed the effect of CRP on risk reclassification in intermediate-risk persons.
Conclusion: Strong evidence indicates that CRP is associated with CHD events. Moderate, consistent evidence suggests that adding CRP to risk prediction models among initially intermediate-risk persons improves risk stratification. However, sufficient evidence that reducing CRP levels prevents CHD events is lacking.
]]>Purpose: To summarize the results of 9 systematic reviews of novel risk factors to help the U.S. Preventive Services Task Force (USPSTF) evaluate the factors' clinical usefulness.
Data Sources: Results from a MEDLINE search for English-language articles published from 1966 to September 2008, using the Medical Subject Heading terms cohort studies and cardiovascular diseases in combination with terms for each risk factor.
Study Selection: Studies were included if the participants had no baseline cardiovascular disease and the investigators adjusted for at least 6 Framingham risk factors.
Data Extraction: Study quality was evaluated by using USPSTF criteria and overall quality of evidence for each risk factor by using a modified version of the Grading of Recommendations, Assessment, Development, and Evaluation framework. Each factor's potential clinical value was evaluated by using a set of criteria that emphasized the importance of the effect of that factor on the reclassification of intermediate-risk persons.
Data Synthesis: 9 systematic reviews were conducted. C-reactive protein (CRP) was the best candidate for use in screening and the most rigorously studied, but evidence that changes in CRP level lead to primary prevention of CHD events is inconclusive. The other evaluated risk factors were coronary artery calcium score as measured by electron-beam computed tomography, lipoprotein(a) level, homocysteine level, leukocyte count, fasting blood glucose, periodontal disease, ankle–brachial index, and carotid intima–media thickness. The availability and validity of the evidence varied considerably across the risk factors in terms of aggregate quality, consistency of findings, and applicability to intermediate-risk persons in the general population. For most risk factors, no studies assessed their usefulness for reclassifying intermediate-risk persons.
Limitations: Because of lack of access to original data, no firm conclusions could be drawn about differences in risk prediction among racial and ethnic groups. The review did not emphasize within-cohort comparisons of multiple risk factors.
Conclusion: The current evidence does not support the routine use of any of the 9 risk factors for further risk stratification of intermediate-risk persons.
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