Long-Term Drug Therapy and Drug Discontinuations and Holidays for Osteoporosis Fracture Prevention: A Systematic Review.

Background: Optimal long-term osteoporosis drug treatment (ODT) is uncertain. Purpose: To summarize the effects of long-term ODT and ODT discontinuation and holidays. Data Sources: Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies. Study Selection: 48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB). Data Extraction: Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy. Data Synthesis: Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE). Limitation: No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays. Conclusion: Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms. Primary Funding Source: National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review.

We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.

Comparative Effectiveness of Newer Medications for Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis.

CONTEXT: Alpha-blockers (ABs) and 5-alpha reductase inhibitors have an established role in treating male lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). Recently, newer drugs have shown promise for this indication. OBJECTIVE: To assess the comparative effectiveness and adverse effects (AEs) of newer drugs to treat LUTS attributed to BPH through a systematic review and meta-analysis. EVIDENCE ACQUISITION: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Ovid Embase bibliographic databases (through June 2016) were hand searches for references of relevant studies. Eligible studies included randomized controlled trials published in English of newer ABs, antimuscarinics, a beta-3 adrenoceptor agonist, phosphodiesterase type-5 inhibitors, or combination therapy with one of these medications as an active comparator. Observational studies of the same agents with a duration ≥1 yr that reported AEs were also included. EVIDENCE SYNTHESIS: We synthesized evidence from 43 randomized controlled trials as well as five observational studies. Based on improvement of mean International Prostate Symptom Score and quality of life scores, the effectiveness of the newer ABs was not different from the older ABs (moderate strength of evidence [SOE]), but had more AEs (low SOE). Antimuscarinics/AB combination therapy had similar outcomes as AB monotherapy (all moderate SOE), but often had more AEs. Phosphodiesterase type-5 inhibitors alone or in combination with ABs had similar or inferior outcomes than ABs alone. Evidence was insufficient for the beta-3 adrenoceptor agonist. For all newer agents, the evidence was generally insufficient to assess long-term efficacy, prevention of symptom progression, or AEs. CONCLUSIONS: None of the drugs or drug combinations newly used to treat LUTS attributed to BPH showed outcomes superior to traditional AB treatment. Given the lack of superior outcomes, the studies' short time-horizon, and less assurance of their safety, their current value in treating LUTS attributable to BPH appears low. PATIENT SUMMARY: In this paper, we reviewed the evidence of newer drugs to treat men with urinary problems attributable to an enlarged prostate. We found none of the new drugs to be better but there was more concern about side effects.

Pharmacologic Treatment of Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

BACKGROUND: Pharmacologic interventions are often prescribed for insomnia disorder. PURPOSE: To assess the benefits, harms, and comparative effectiveness of pharmacologic treatments for adults with insomnia disorder. DATA SOURCES: Several electronic databases (2004-September 2015), reference lists, and U.S. Food and Drug Administration (FDA) documents. STUDY SELECTION: 35 randomized, controlled trials of at least 4 weeks' duration that evaluated pharmacotherapies available in the United States and that reported global or sleep outcomes; 11 long-term observational studies that reported harm information; FDA review data for nonbenzodiazepine hypnotics and orexin receptor antagonists; and product labels for all agents. DATA EXTRACTION: Data extraction by single investigator confirmed by a second reviewer; dual-investigator assessment of risk of bias; consensus determination of strength of evidence. DATA SYNTHESIS: Eszopiclone, zolpidem, and suvorexant improved short-term global and sleep outcomes compared with placebo, although absolute effect sizes were small (low- to moderate-strength evidence). Evidence for benzodiazepine hypnotics, melatonin agonists, and antidepressants, and for most pharmacologic interventions in older adults, was insufficient or low strength. Evidence was also insufficient to compare efficacy within or across pharmacotherapy classes or versus behavioral therapy. Harms evidence reported in trials was judged insufficient or low strength; observational studies suggested that use of hypnotics for insomnia was associated with increased risk for dementia, fractures, and major injury. The FDA documents reported that most pharmacotherapies had risks for cognitive and behavioral changes, including driving impairment, and other adverse effects, and they advised dose reduction in women and in older adults. LIMITATIONS: Most trials were small and short term and enrolled individuals meeting stringent criteria. Minimum important differences in outcomes were often not established or reported. Data were scant for many treatments. CONCLUSION: Eszopiclone, zolpidem, and suvorexant may improve short-term global and sleep outcomes for adults with insomnia disorder, but the comparative effectiveness and long-term efficacy of pharmacotherapies for insomnia are not known. Pharmacotherapies for insomnia may cause cognitive and behavioral changes and may be associated with infrequent but serious harms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. ( PROSPERO: CRD42014009908).

Psychological and Behavioral Interventions for Managing Insomnia Disorder: An Evidence Report for a Clinical Practice Guideline by the American College of Physicians.

BACKGROUND: Psychological and behavioral interventions are frequently used for insomnia disorder. PURPOSE: To assess benefits and harms of psychological and behavioral interventions for insomnia disorder in adults. DATA SOURCES: Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO through September 2015, supplemented with hand-searching. STUDY SELECTION: Randomized, controlled trials of psychological or behavioral interventions that were published in English and enrolled adults with insomnia disorder lasting 4 or more weeks. DATA EXTRACTION: Data extraction by single investigator confirmed by a second reviewer; dual investigator assessment of risk of bias; consensus determination of strength of evidence. DATA SYNTHESIS: Sixty trials with low to moderate risk of bias compared psychological and behavioral interventions with inactive controls or other psychological and behavioral interventions. Cognitive behavioral therapy for insomnia (CBT-I) improved posttreatment global and most sleep outcomes, often compared with information or waitlist controls (moderate-strength evidence). Use of CBT-I improved several sleep outcomes in older adults (low- to moderate-strength evidence). Multicomponent behavioral therapy improved several sleep outcomes in older adults (low- to moderate-strength evidence). Stimulus control improved 1 or 2 sleep outcomes (low-strength evidence). Evidence for other comparisons and for harms was insufficient to permit conclusions. LIMITATIONS: A wide variety of comparisons limited the ability to pool data. Trials did not always report global outcomes and infrequently conducted remitter or responder analysis. Comparisons were often information or waitlist groups, and publication bias was possible. CONCLUSION: Use of CBT-I improves most outcomes compared with inactive controls. Multicomponent behavioral therapy and stimulus control may improve some sleep outcomes. Evidence on other outcomes, comparisons, and long-term efficacy were limited. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. ( PROSPERO: CRD42014009908).

Intermediate- and Long-Term Cognitive Outcomes After Cardiovascular Procedures in Older Adults: A Systematic Review.

BACKGROUND: Risks for intermediate- and long-term cognitive impairment after cardiovascular procedures in older adults are poorly understood. PURPOSE: To summarize evidence about cognitive outcomes in adults aged 65 years or older at least 3 months after coronary or carotid revascularization, cardiac valve procedures, or ablation for atrial fibrillation. DATA SOURCES: MEDLINE, Cochrane, and Scopus databases from 1990 to January 2015; ClinicalTrials.gov; and bibliographies of reviews and eligible studies. STUDY SELECTION: English-language trials and prospective cohort studies. DATA EXTRACTION: One reviewer extracted data, a second checked accuracy, and 2 independently rated quality and strength of evidence (SOE). DATA SYNTHESIS: 17 trials and 4 cohort studies were included; 80% of patients were men, and mean age was 68 years. Cognitive function did not differ after the procedure between on- and off-pump coronary artery bypass grafting (CABG) (n = 6; low SOE), hypothermic and normothermic CABG (n = 3; moderate to low SOE), or CABG and medical management (n = 1; insufficient SOE). One trial reported lower risk for incident cognitive impairment with minimal versus conventional extracorporeal CABG (risk ratio, 0.34 [95% CI, 0.16 to 0.73]; low SOE). Two trials found no difference between surgical carotid revascularization and carotid stenting or angioplasty (low and insufficient SOE, respectively). One cohort study reported increased cognitive decline after transcatheter versus surgical aortic valve replacement but had large selection and outcome measurement biases (insufficient SOE). LIMITATIONS: Mostly low to insufficient SOE; no pertinent data for ablation; limited generalizability to the most elderly patients, women, and persons with substantial baseline cognitive impairment; and possible selective reporting and publication bias. CONCLUSION: Intermediate- and long-term cognitive impairment in older adults attributable to the studied cardiovascular procedures may be uncommon. Nevertheless, clinicians counseling patients before these procedures should discuss the uncertainty in their risk for adverse cognitive outcomes. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force.

BACKGROUND: Screening for peripheral artery disease (PAD) may reduce morbidity and mortality. PURPOSE: To review the evidence on the ability of the ankle-brachial index (ABI) to predict cardiovascular disease (CVD) morbidity and mortality independent of Framingham Risk Score (FRS) factors in asymptomatic adults and on the benefits and harms of treating screen-detected adults with PAD. DATA SOURCES: MEDLINE and the Cochrane Central Register of Controlled Trials (1996 to September 2012), clinical trial registries, reference lists, and experts. STUDY SELECTION: English-language, population-based prognostic studies evaluating the ABI in addition to the FRS and treatment trials or studies of treatment harms in screen-detected adults with PAD. DATA EXTRACTION: Dual quality assessment and abstraction of relevant study details. DATA SYNTHESIS: One large meta-analysis (n = 43 919) showed that the ABI could reclassify 10-year risk for coronary artery disease (CAD), but it did not report measures of appropriate reclassification (the net reclassification improvement [NRI]). Four heterogeneous risk prediction studies showed that the magnitude of the NRI was probably small when the ABI was added to the FRS to predict CAD or CVD events. Of 2 treatment trials meeting inclusion criteria, 1 large trial (n = 3350) showed that low-dose aspirin did not prevent CVD events in persons with a screen-detected low ABI but may have increased the risk for major bleeding events. LIMITATIONS: Most prognostic studies did not allow for calculation of a bias-corrected NRI. Evidence on treatment benefits and harms was limited to aspirin and was scant. CONCLUSION: Adding the ABI to the FRS probably has limited value for predicting CAD or CVD. Treatment benefits for asymptomatic individuals with screen-detected PAD are not established. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Association of first- and second-generation air bags with front occupant death in car crashes: a matched cohort study.

First-generation air bags entail a decreased risk of death for most front seat occupants in car crashes but an increased risk for children. Second-generation air bags were developed to reduce the risks for children, despite the possibility of decreasing protection for others. Using a matched cohort design, the authors estimated risk ratios for death for use of each generation of air bag versus no air bag, adjusted for seat position, restraint use, sex, age, and all vehicle and crash characteristics, among 128,208 automobile occupants involved in fatal crashes on US roadways during 1990-2002. The authors then compared adjusted risk ratios (aRRs) between the two generations of air bags. Among front seat occupants, the aRR for death with a first-generation air bag was 0.90 (95% confidence interval (CI): 0.86, 0.94); the aRR with a second-generation air bag was 0.89 (95% CI: 0.79, 1.00) (p = 0.83 for comparison of aRRs). Among children under age 6 years, the aRR with a first-generation air bag was 1.66 (95% CI: 1.20, 2.30), while the aRR with a second-generation air bag was 1.10 (95% CI: 0.63, 1.93) (p = 0.20 for comparison of aRRs). The differences in aRRs between first- and second-generation air bags among other subgroups were small and not statistically significant.

Intravenous magnesium for acute benign headache in the emergency department: a randomized double-blind placebo-controlled trial.

BACKGROUND: Magnesium deficiency may play a role in the pathogenesis of migraines and other headaches. Studies in outpatient clinics have found that magnesium administered intravenously (IV) reduces headache pain. We investigated the effectiveness of IV magnesium in patients with acute benign headache who presented to the emergency department (ED). METHODS: This randomized double-blind placebo-controlled trial compared 2 g of IV magnesium versus placebo for the treatment of patients with acute benign headache who presented to the EDs of two teaching hospitals. Pre- and post-treatment pain scores were measured on a 100-mm visual analog pain scale. RESULTS: Forty-two patients were randomized, 21 in each treatment group. Treatment groups had similar baseline characteristics. After treatment, placebo recipients reported an 8-mm median improvement in pain, and magnesium recipients had a 3-mm improvement (p = 0.63). We found no statistically significant difference between groups for any secondary outcomes; however, the patients who received magnesium had significantly (p = 0.03) more side effects than did those in the placebo group. CONCLUSIONS: We found no benefit to using IV magnesium to treat patients with acute benign headache who present to the ED.

Publication bias in editorial decision making.

CONTEXT: Studies with positive results are more likely to be published than studies with negative results (publication bias). One reason this occurs is that authors are less likely to submit manuscripts reporting negative results to journals. There is no evidence that publication bias occurs once manuscripts have been submitted to a medical journal. We assessed whether submitted manuscripts that report results of controlled trials are more likely to be published if they report positive results. METHODS: Prospective cohort study of manuscripts submitted to JAMA from February 1996 through August 1999. We classified results as positive if there was a statistically significant difference (P<.05) reported for the primary outcome. Study characteristics and indicators for quality were also appraised. We included manuscripts that reported prospective studies in which participants were assigned to an intervention or comparison group and statistical tests compared differences between groups. RESULTS: Among 745 manuscripts, 133 (17.9%) were published: 78 (20.4%) of 383 with positive results, 51 (15.0%) of 341 with negative results, and 4 (19.0%) of 21 with unclear results. The crude relative risk for publication of studies with positive results compared with negative results was 1.36 (95% confidence interval [CI], 0.99-1.88). After being adjusted simultaneously for study characteristics and quality indicators, the odds ratio for publishing studies with positive results was 1.30 (95% CI, 0.87-1.96). CONCLUSIONS: Among submitted manuscripts, we did not find a statistically significant difference in publication rates between those with positive vs negative results.

Association between time interval to publication and statistical significance.

CONTEXT: Studies have shown that reports from clinical trials with statistically significant results tend to be submitted and published more rapidly than reports from studies with null or insignificant findings. METHODS: We wanted to determine whether manuscripts reporting positive results from controlled clinical trials are published more quickly than those reporting negative results. We tracked manuscripts from submission to JAMA until the publication decision. We classified results as positive if a statistically significant difference was reported for the primary outcome. Manuscripts were further classified according to indicators of methodologic quality and other study characteristics. We included manuscripts if they were submitted from February 1996 through August 1999, reported results of a prospective study in which participants were assigned to a treatment or comparison group, used statistical tests to compare differences between groups, and were accepted for publication. RESULTS: One hundred thirty-three manuscripts met our inclusion criteria, 78 (59%) reported positive results, 51 (38%) reported negative results. We were unable to classify the direction of results for 4 articles (3%). The time interval between submission and publication was not associated with positive results: median time between submission and publication was 7.8 months for reports with positive vs 7.6 months for reports with negative results (P =.44). Time to publication also was not associated with any marker of study quality or study characteristic. CONCLUSIONS: Among 133 published controlled trials, time to publication was not associated with statistical significance, methodologic quality, or other study characteristics.