Oxygen for relief of dyspnoea in people with chronic obstructive pulmonary disease who would not qualify for home oxygen: a systematic review and meta-analysis.

We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register to determine whether oxygen relieves dyspnoea in mildly or non-hypoxemic COPD and included 18 randomised controlled trials (431 participants) in the meta-analysis using Cochrane methodology. Oxygen therapy reduced dyspnoea when compared with medical air; standardised mean difference -0.37 (95% CI -0.50 to -0.24; I(2)=14%). In a priori subgroup and sensitivity analyses, dyspnoea was reduced by continuous oxygen during exertion but not short-burst oxygen therapy. Continuous exertional oxygen can relieve dyspnoea in mildly or non-hypoxemic COPD, but evidence from larger clinical trials is needed.

Antiepileptics in migraine prophylaxis: an updated Cochrane review.

INTRODUCTION: The efficacy of several antiepileptics in the preventive treatment of episodic migraine in adults has been systematically reviewed. Because many trial reports have been published since then, an updated systematic review was warranted. METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed/MEDLINE (1966 to January 15, 2013), MEDLINE In-Process (current week, January 15, 2013), and EMBASE (1974 to January 15, 2013) and hand-searched Headache and Cephalalgia through January 2013. Prospective, controlled trials of antiepileptics taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both, were selected. RESULTS: Mean headache frequency on topiramate and sodium valproate is significantly lower than placebo. Likewise, topiramate and divalproex demonstrated favorable results for the proportion of subjects with ≥ 50% reduction of migraine attacks. For topiramate, 100 mg and 200 mg outperformed 50 mg, but this was paralleled by a higher adverse event rate. For valproate/divalproex, a dose-effect correlation could not be established. There was no unequivocal evidence of efficacy for any of the other antiepileptics. CONCLUSION: Topiramate, sodium valproate and divalproex are effective prophylactic treatments for episodic migraine in adults. In contrast to previous reports, there is insufficient evidence to further support the use of gabapentin.

Prioritization of research addressing management strategies for ductal carcinoma in situ.

Ductal carcinoma in situ is a common finding in women having mammography screening, and there is considerable uncertainty about the balance of harms and benefits of different management options. This article outlines the process for developing a prioritized research agenda for the Patient-Centered Outcomes Research Institute as informed by a diverse group of stakeholders on the management of ductal carcinoma in situ. Evidence gaps were identified by reviewing existing literature and engaging diverse stakeholders to refine these gaps. Stakeholders ranked evidence gaps by importance from their perspectives using a forced-ranking prioritization method. PubMed was searched for relevant recent studies, and ClinicalTrials.gov was searched for relevant ongoing trials for the 10 highest-ranked evidence gaps. Strengths and limitations of different study designs were assessed to address gaps. Stakeholders prioritized evidence gaps related to incorporation of patient-centered outcomes into future research, development of better methods to predict risk for invasive cancer, evaluation of a strategy of active surveillance, and testing of decision-making tools. The degree to which prioritized evidence gaps may have already been addressed is uncertain because a comprehensive systematic review has not been done.

Prioritization of patient-centered comparative effectiveness research for osteoarthritis.

Osteoarthritis is a leading cause of disability in the United States. This article describes a prioritized research agenda about osteoarthritis management developed for the Patient-Centered Outcomes Research Institute. Evidence gaps were identified by reviewing existing literature and engaging diverse stakeholders to expand and refine gaps. Stakeholders ranked evidence gaps by importance from their perspectives.Prioritized evidence gaps included the need to determine or evaluate key patient-centered outcomes; optimal duration, intensity, and frequency of nonsurgical interventions; whether the comparative effectiveness of nonsurgical interventions varies by socioeconomic factors; when and how to transition from nonsurgical to surgical interventions; effective ways to engage patients in self-management and promote long-term behavior change; standardized screening tools that improve early diagnosis; biomechanical strategies that improve symptoms; mechanisms for promoting and delivering coordinated, longitudinal care; and comparative effectiveness of nonsurgical therapies. Searches of PubMed and ClinicalTrials.gov showed many recent and ongoing studies addressing comparative effectiveness of nonsurgical interventions; relatively few of these evaluated treatments across categories (for example, drug therapy vs. weight management) or combined categories of treatment. Few studies addressed other high-priority evidence gaps.

Prioritization of research addressing antipsychotics for adolescents and young adults with bipolar disorder.

Despite a paucity of high-quality evidence about benefits and harms, antipsychotic medication use among adolescents and young adults with bipolar disorder is increasing. The Patient-Centered Outcomes Research Institute tasked the Duke Evidence Synthesis Group with creating a prioritized agenda for research in this area that would incorporate the perspectives of relevant stakeholders. We identified a list of potential evidence gaps by reviewing existing literature and engaged a diverse group of 9 stakeholders to expand and refine this list. Using a forced-ranking prioritization method, stakeholders prioritized 10 of 23 potential evidence gaps as the most pressing for future research. These evidence gaps relate to 3 areas: the comparative effectiveness of intervention strategies, the effect of antipsychotics on patient-centered outcomes, and the influence of various patient characteristics on antipsychotic effectiveness. In addition to presenting these findings, we suggest appropriate study designs for addressing the stakeholder-prioritized research questions.

Benefits and Harms of Breast Cancer Screening: A Systematic Review.

IMPORTANCE: Patients need to consider both benefits and harms of breast cancer screening. OBJECTIVE: To systematically synthesize available evidence on the association of mammographic screening and clinical breast examination (CBE) at different ages and intervals with breast cancer mortality, overdiagnosis, false-positive biopsy findings, life expectancy, and quality-adjusted life expectancy. EVIDENCE REVIEW: We searched PubMed (to March 6, 2014), CINAHL (to September 10, 2013), and PsycINFO (to September 10, 2013) for systematic reviews, randomized clinical trials (RCTs) (with no limit to publication date), and observational and modeling studies published after January 1, 2000, as well as systematic reviews of all study designs. Included studies (7 reviews, 10 RCTs, 72 observational, 1 modeling) provided evidence on the association between screening with mammography, CBE, or both and prespecified critical outcomes among women at average risk of breast cancer (no known genetic susceptibility, family history, previous breast neoplasia, or chest irradiation). We used summary estimates from existing reviews, supplemented by qualitative synthesis of studies not included in those reviews. FINDINGS: Across all ages of women at average risk, pooled estimates of association between mammography screening and mortality reduction after 13 years of follow-up were similar for 3 meta-analyses of clinical trials (UK Independent Panel: relative risk [RR], 0.80 [95% CI, 0.73-0.89]; Canadian Task Force: RR, 0.82 [95% CI, 0.74-0.94]; Cochrane: RR, 0.81 [95% CI, 0.74-0.87]); were greater in a meta-analysis of cohort studies (RR, 0.75 [95% CI, 0.69 to 0.81]); and were comparable in a modeling study (CISNET; median RR equivalent among 7 models, 0.85 [range, 0.77-0.93]). Uncertainty remains about the magnitude of associated mortality reduction in the entire US population, among women 40 to 49 years, and with annual screening compared with biennial screening. There is uncertainty about the magnitude of overdiagnosis associated with different screening strategies, attributable in part to lack of consensus on methods of estimation and the importance of ductal carcinoma in situ in overdiagnosis. For women with a first mammography screening at age 40 years, estimated 10-year cumulative risk of a false-positive biopsy result was higher (7.0% [95% CI, 6.1%-7.8%]) for annual compared with biennial (4.8% [95% CI, 4.4%-5.2%]) screening. Although 10-year probabilities of false-positive biopsy results were similar for women beginning screening at age 50 years, indirect estimates of lifetime probability of false-positive results were lower. Evidence for the relationship between screening and life expectancy and quality-adjusted life expectancy was low in quality. There was no direct evidence for any additional mortality benefit associated with the addition of CBE to mammography, but observational evidence from the United States and Canada suggested an increase in false-positive findings compared with mammography alone, with both studies finding an estimated 55 additional false-positive findings per extra breast cancer detected with the addition of CBE. CONCLUSIONS AND RELEVANCE: For women of all ages at average risk, screening was associated with a reduction in breast cancer mortality of approximately 20%, although there was uncertainty about quantitative estimates of outcomes for different breast cancer screening strategies in the United States. These findings and the related uncertainty should be considered when making recommendations based on judgments about the balance of benefits and harms of breast cancer screening.

Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults.

BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between antiepileptic drugs and comparators (placebo, active control, or same drug in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4). AUTHORS' CONCLUSIONS: Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations.

Topiramate for the prophylaxis of episodic migraine in adults.

BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of topiramate for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of topiramate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between topiramate and comparator (placebo, active control, or topiramate in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and, in select cases, risk ratios (RRs); we also calculated numbers needed to treat (NNTs). We calculated MDs for selected quality of life instruments. Finally, we summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Twenty papers describing 17 unique trials met the inclusion criteria. Analysis of data from nine trials (1737 participants) showed that topiramate reduced headache frequency by about 1.2 attacks per 28 days as compared to placebo (MD -1.20; 95% confidence interval (CI) -1.59 to -0.80). Data from nine trials (1190 participants) show that topiramate approximately doubled the proportion of responders relative to placebo (RR 2.02; 95% CI 1.57 to 2.60; NNT 4; 95% CI 3 to 6). Separate analysis of different topiramate doses produced similar MDs versus placebo at 50 mg (-0.95; 95% CI -1.95 to 0.04; three studies; 520 participants), 100 mg (-1.15; 95% CI -1.58 to -0.71; six studies; 1620 participants), and 200 mg (-0.94; 95% CI -1.53 to -0.36; five studies; 804 participants). All three doses significantly increased the proportion of responders relative to placebo; ORs were as follows: for 50 mg, 2.35 (95% CI 1.60 to 3.44; three studies; 519 participants); for 100 mg, 3.49 (95% CI 2.23 to 5.45; five studies; 852 participants); and for 200 mg, 2.49 (95% CI 1.61 to 3.87; six studies; 1025 participants). All three doses also significantly improved three or more domains of quality of life as compared to placebo. Meta-analysis of the three studies that included more than one dose of topiramate suggests that 200 mg is no more effective than 100 mg. With regard to mean headache frequency and/or responder rate, seven trials using active comparators found (a) no significant difference between topiramate and amitriptyline (one study, 330 participants); (b) no significant difference between topiramate and flunarizine (one study, 83 participants); (c) no significant difference between topiramate and propranolol (two studies, 342 participants); (d) no significant difference between topiramate and relaxation (one study, 61 participants); but (e) a slight significant advantage of topiramate over valproate (two studies, 120 participants). Relaxation improved migraine-specific quality of life significantly more than topiramate. In trials of topiramate against placebo, seven adverse events (AEs) were reported by at least three studies. These were usually mild and of a non-serious nature. Except for taste disturbance and weight loss, there were no significant differences in the frequency of AEs in general, or of the seven specific AEs, between placebo and topiramate 50 mg. AEs in general and all of the specific AEs except nausea were significantly more common on topiramate 100 mg than on placebo, with NNHs varying from 3 to 25, and the RDs versus placebo were even higher for topiramate 200 mg, with NNHs varying from 2 to 17. AUTHORS' CONCLUSIONS: Meta-analysis demonstrates that topiramate in a 100 mg/day dosage is effective in reducing headache frequency and reasonably well-tolerated in adult patients with episodic migraine. This provides good evidence to support its use in routine clinical management. More studies designed specifically to compare the efficacy or safety of topiramate versus other interventions with proven efficacy in the prophylaxis of migraine are needed.

Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults.

BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of gabapentin/gabapentin enacarbil or pregabalin for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of gabapentin/gabapentin enacarbil or pregabalin taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between gabapentin and comparator (placebo, active control, or gabapentin in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from all single dosage studies and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Five trials on gabapentin and one trial on its prodrug gabapentin enacarbil met the inclusion criteria; no reports on pregabalin were identified. In total, data from 1009 patients were considered. One trial each of gabapentin 900 mg (53 patients), and gabapentin titrated to 1200 mg (63 patients) and 1800 mg (122 patients) failed to show a statistically significant reduction in headache frequency in the active treatment group as compared to the placebo group, whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (MD -0.80; 95% confidence interval (CI) -1.55 to -0.05). The pooled results of these four studies (MD -0.44; 95% CI -1.43 to 0.56; 351 patients) do not demonstrate a significant difference between gabapentin and placebo. One trial of gabapentin titrated to 1800 mg (122 patients) failed to demonstrate a significant difference between active treatment and placebo in the proportion of responders (OR 0.97; 95% CI 0.45 to 2.11), whereas one trial of gabapentin titrated to 1800 to 2400 mg (113 patients) demonstrated a small but statistically significant superiority of active treatment for this outcome (OR 2.79; 95% CI 1.09 to 7.17). The pooled results of these two studies (OR 1.59; 95% CI 0.57 to 4.46; 235 patients) do not demonstrate a significant difference between gabapentin and placebo. Comparisons from one study (135 patients) suggest that gabapentin 2000 mg is no more effective than gabapentin 1200 mg. One trial of gabapentin enacarbil (523 participants) failed to demonstrate a significant difference versus placebo or between doses for gabapentin enacarbil titrated to between 1200 mg and 3000 mg with regard to proportion of responders; there was also no evidence of a dose-response trend. Adverse events, most notably dizziness and somnolence, were common with gabapentin. AUTHORS' CONCLUSIONS: The pooled evidence derived from trials of gabapentin suggests that it is not efficacious for the prophylaxis of episodic migraine in adults. Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice. Gabapentin enacarbil is not efficacious for the prophylaxis of episodic migraine in adults. There is no published evidence from controlled trials of pregabalin for the prophylaxis of episodic migraine in adults.

Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults.

BACKGROUND: Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007. OBJECTIVES: To describe and assess the evidence from controlled trials on the efficacy and tolerability of valproate (valproic acid or sodium valproate or a combination of the two) for preventing migraine attacks in adult patients with episodic migraine. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013. SELECTION CRITERIA: Studies were required to be prospective, controlled trials of valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between valproate and comparator (placebo, active control, or valproate in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and, in select cases, risk ratios (RRs); we also calculated numbers needed to treat (NNTs). We calculated MDs for Migraine Disability Assessment (MIDAS) scores. We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs). MAIN RESULTS: Ten papers describing 10 unique trials met the inclusion criteria. Analysis of data from two trials (63 participants) showed that sodium valproate reduced headache frequency by approximately four headaches per 28 days as compared to placebo (MD -4.31; 95% confidence interval (CI) -8.32 to -0.30). Data from four trials (542 participants) showed that divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) more than doubled the proportion of responders relative to placebo (RR 2.18; 95% CI 1.28 to 3.72; NNT 4; 95% CI 2 to 11). One study of sodium valproate (34 participants) versus placebo supported the latter findings (RR for responders 2.83; 95% CI 1.27 to 6.31; NNT 3; 95% CI 2 to 9). There was no significant difference in the proportion of responders between sodium valproate versus flunarizine (one trial, 41 participants) or between divalproex sodium versus propranolol (one trial, 32 participants). Pooled analysis of post-treatment mean headache frequencies in two trials (88 participants) demonstrates a slight but significant advantage for topiramate 50 mg over valproate 400 mg (MD -0.90; 95% CI -1.58 to -0.22). For placebo-controlled trials of sodium valproate and divalproex sodium, NNHs for clinically important adverse events ranged from 7 to 14. AUTHORS' CONCLUSIONS: Valproate is effective in reducing headache frequency and is reasonably well tolerated in adult patients with episodic migraine.

WITHDRAWN: Oral sumatriptan for acute migraine.

BACKGROUND: Migraine is a common neurovascular disorder characterized by recurrent episodes of disabling headache, autonomic nervous system dysfunction, and, in some patients, neurological aura symptoms. Sumatriptan is one of a class of selective serotonin 5-hydroxytryptamine (5-HT1B/1D) agonists (triptans) thought to relieve migraine attacks by several mechanisms, including cranial vasoconstriction and peripheral and central neural inhibition. OBJECTIVES: To describe and assess the evidence from randomized controlled trials (RCTs) concerning the efficacy and tolerability of oral sumatriptan for the treatment of a single acute attack of migraine in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (Cochrane Library, Issue 4, 2001), MEDLINE (1966 through November 2001), and reference lists of articles and books. SELECTION CRITERIA: We included double-blind RCTs comparing oral sumatriptan (100 mg, 50 mg, 25 mg) with placebo, no intervention, other drug treatments, behavioral therapy, or physical therapy for the treatment of an acute attack of migraine in adults. Trials comparing different doses of sumatriptan or dosing regimens were also included. Outcomes considered were: 2-hour pain-free response, headache relief/headache intensity, and functional disability; headache recurrence; and adverse events. DATA COLLECTION AND ANALYSIS: Data were abstracted by one reviewer and over-read by the other. The two reviewers independently assessed trial quality. Information on adverse events was collected from trial reports. MAIN RESULTS: Twenty-five trials involving 16,200 participants were included. Methodological quality was generally good. Sixteen trials were placebo comparisons and showed that sumatriptan in doses of 100 mg (14 trials), 50 mg (five trials), and 25 mg (three trials) provided significantly better pain-free response (100 mg and 25 mg only), headache relief, and relief of disability at 2 hours. Numbers-needed-to-treat (NNTs) for pain-free response at 2 hours were 5.1 (3.9 to 7.1) for the 100-mg dose (n = 2221) and 7.5 (2.7 to 142) for the 25-mg dose (n = 131); there was no significant difference between the 50-mg dose and placebo for this outcome (n = 127). For headache relief at 2 hours, NNTs were 3.4 (3.0 to 4.0), 3.2 (2.4 to 5.1), and 3.4 (2.3 to 6.6) for sumatriptan 100 mg (n = 2940), 50 mg (n = 420), and 25 mg (n = 226), respectively. Precise estimates of the efficacy of the 50- and 25-mg doses relative to the 100-mg dose could not be obtained.Adverse events were more common with sumatriptan 100 mg than with placebo (risk difference [RD] = 0.14 [0.09 to 0.20]; number-needed-to-harm [NNH] = 7.1 [5.0 to 11.1]; n = 3172). RDs for the 50- and 25-mg vs. placebo comparisons were not statistically significant. AUTHORS' CONCLUSIONS: Oral sumatriptan has been shown to be an effective drug for the treatment of a single acute attack of migraine. It is well tolerated, though minor adverse events were not uncommon in the included trials. Other triptans were generally similar in efficacy and adverse events. Among non-triptan drugs, ergotamine + caffeine was significantly less effective than sumatriptan, and other drugs have been insufficiently studied to draw firm conclusions.

Symptomatic oxygen for non-hypoxaemic chronic obstructive pulmonary disease.

BACKGROUND: Dyspnoea is a common symptom in chronic obstructive pulmonary disease (COPD). People who are hypoxaemic may be given long-term oxygen relief therapy (LTOT) to improve their life expectancy and quality of life. However, the symptomatic benefit of home oxygen therapy in mildly or non-hypoxaemic people with COPD with dyspnoea who do not meet international funding criteria for LTOT (PaO(2)< 55 mmHg or other special cases) is unknown. OBJECTIVES: To determine the efficacy of oxygen versus medical air for relief of subjective dyspnoea in mildly or non-hypoxaemic people with COPD who would not otherwise qualify for home oxygen therapy. The main outcome was patient-reported dyspnoea and secondary outcome was exercise tolerance. SEARCH STRATEGY: We searched the Cochrane Airways Group Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, to November 2009, to identify randomised controlled trials. We handsearched reference lists of included articles. SELECTION CRITERIA: We only included randomised controlled trials of oxygen versus medical air in mildly or non-hypoxaemic people with COPD. Two review authors independently assessed articles for inclusion. DATA COLLECTION AND ANALYSIS: One review author completed data extraction and methodological quality assessment. A second review author then over-read evidence tables to assess for accuracy. MAIN RESULTS: Twenty-eight trials on 702 patients met the criteria for inclusion; 18 trials (431 participants) were included in the meta-analysis. Oxygen reduced dyspnoea with a standardised mean difference (SMD) of -0.37 (95% confidence interval (CI) -0.50 to -0.24, P < 0.00001). We observed significant heterogeneity. AUTHORS' CONCLUSIONS: Oxygen can relieve dyspnoea in mildly and non-hypoxaemic people with COPD who would not otherwise qualify for home oxygen therapy. Given the significant heterogeneity among the included studies, clinicians should continue to evaluate patients on an individual basis until supporting data from ongoing, large randomised controlled trials are available.

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

BACKGROUND: The Centers for Medicare & Medicaid Services limit coverage of cancer drugs for off-label indications to indications listed in specified compendia. PURPOSE: To assess whether compendia provide comprehensive, research-based, and timely information for off-label prescribing in oncology. DATA SOURCES: 6 drug compendia, English-language literature searches of MEDLINE and the Cochrane Central Register of Controlled Trials from 2006 and 2008, and American Society of Clinical Oncology annual meeting abstracts from 2004 to 2007. Data Assessment: The compendia's stated methods, literature related to off-label indications of 14 cancer drugs in 2006, updated literature related to 1 off-label indication between 2006 and 2008, and completeness of compendia content and citations were assessed. DATA SYNTHESIS: The compendia's stated methods varied greatly from their actual practices. Compendia cited little of the available evidence, often neither the most recent nor that of highest methodological quality. Compendia differed in evidence cited, terminology, detail, presentation, and referencing. For the 14 off-label indications studied, the compendia differed in the indications included and whether and how they recommended particular agents for particular types of cancer. Update schedules varied, and documentation practices made it difficult to determine whether and when compendia content was updated. For 1 indication, compendia citations did not increase between 2006 and 2008 despite newly published articles. LIMITATIONS: The 2006 analysis was limited to 14 off-label indications; the 2008 update examined 1 indication. Only off-label indications for cancer drugs were included, and results cannot be generalized to noncancer drugs or indications. CONCLUSION: Oncologists rely on compendia for up-to-date access to evidence and reimbursement information for off-label indications. Current compendia lack transparency, cite little current evidence, and lack systematic methods to review or update evidence.

Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: a systematic review.

OBJECTIVE: Children admitted to pediatric intensive care units (PICUs) often receive sedatives to facilitate mechanical ventilation. However, despite their widespread use, data supporting appropriate dosing, safety, and optimal regimens for sedation during mechanical ventilation are lacking. Therefore, we conducted a systematic review of published data regarding efficacy of sedation to facilitate mechanical ventilation in PICU patients. Our primary objective was to identify and evaluate the quality of evidence supporting sedatives used in PICUs for this purpose. DATA SOURCES: We searched MEDLINE, EMBASE, and The Cochrane Registry of Clinical Trials from 1966 to June 2008 to identify published articles evaluating sedation regimens to facilitate mechanical ventilation in PICU patients. STUDY SELECTION: We included only those studies of intubated PICU or pediatric cardiac intensive care unit patients receiving pharmacologic agents to facilitate mechanical ventilation that reported quality of sedation as an outcome. DATA EXTRACTION: We analyzed studies separately for study type and by agents being studied. Studies were appraised using criteria of particular importance for reviews evaluating sedatives. DATA SYNTHESIS: Our search strategy yielded 39 studies, including 3 randomized trials, 15 cohort studies, and 21 cases series or reports. The 39 studies evaluated a total of 39 different sedation regimens, with 21 different scoring systems, in a total of 901 PICU/cardiac intensive care unit patients ranging in age from 3 days to 19 years old. Most of the studies were small (<30 patients), and only four studies compared one or more agents to another. Few studies thoroughly evaluated drug safety, and only one study met all quality criteria. CONCLUSIONS: Despite the widespread use of sedatives to facilitate mechanical ventilation in the PICU, we found that high-quality evidence to guide clinical practice is still limited. Pediatric randomized, controlled trials with reproducible methods and assessment of drug safety are needed.

Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension.

BACKGROUND: The relative effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) for lowering blood pressure is unknown. PURPOSE: To compare the benefits and harms of ACE inhibitors versus ARBs for treating essential hypertension in adults. DATA SOURCES: MEDLINE (1966 to May 2006), the Cochrane Central Register of Controlled Trials (Issue 2, 2006), and selected reference lists were searched for relevant English-language trials. The MEDLINE search was updated to August 2007 to identify head-to-head trials that reported blood pressure outcomes and major cardiovascular events. STUDY SELECTION: 61 clinical studies that directly compared ACE inhibitors versus ARBs in adult patients with essential hypertension, reported an outcome of interest, lasted at least 12 weeks, and included at least 20 patients. DATA EXTRACTION: A standardized protocol with predefined criteria was used to extract data on study design, interventions, population characteristics, and outcomes; evaluate study quality and applicability; and assess the strength of the body of evidence for key outcomes. DATA SYNTHESIS: ACE inhibitors and ARBs had similar long-term effects on blood pressure (50 studies; strength of evidence, high). No consistent differential effects were observed for other outcomes (few studies reported long-term outcomes), including death, cardiovascular events, quality of life, rate of single antihypertensive agent use, lipid levels, progression to diabetes, left ventricular mass or function, and kidney disease. Consistent fair- to good-quality evidence showed that ACE inhibitors were associated with a greater risk for cough. There were fewer withdrawals due to adverse events and greater persistence with therapy for ARBs than for ACE inhibitors, although this evidence was not definitive. Patient subgroups for whom ACE inhibitors or ARBs were more effective, associated with fewer adverse events, or better tolerated were not identified. LIMITATIONS: Few studies involved a representative sample treated in a typical clinical setting over a long duration, treatment protocols had marked heterogeneity, and substantive amounts of data about important outcomes and patient subgroups were missing. CONCLUSION: Available evidence shows that ACE inhibitors and ARBs have similar effects on blood pressure control, and that ACE inhibitors have higher rates of cough than ARBs. Data regarding other outcomes are limited.

Flunarizine as prophylaxis for episodic migraine: a systematic review with meta-analysis.

Based on few clinical trials, flunarizine is considered a first-line prophylactic treatment for migraine in several guidelines. In this meta-analysis, we examined the pooled evidence for its effectiveness, tolerability, and safety. Prospective randomized controlled trials of flunarizine as a prophylaxis against migraine were identified from a systematic literature search, and risk of bias was assessed for all included studies. Reduction in mean attack frequency was estimated by calculating the mean difference (MD), and a series of secondary outcomes-including adverse events (AEs)-were also analyzed. The database search yielded 879 unique records. Twenty-five studies were included in data synthesis. We scored 31/175 risk of bias items as "high," with attrition as the most frequent bias. A pooled analysis estimated that flunarizine reduces the headache frequency by 0.4 attacks per 4 weeks compared with placebo (5 trials, 249 participants: MD -0.44; 95% confidence interval -0.61 to -0.26). Analysis also revealed that the effectiveness of flunarizine prophylaxis is comparable with that of propranolol (7 trials, 1151 participants, MD -0.08; 95% confidence interval -0.34 to 0.18). Flunarizine also seems to be effective in children. The most frequent AEs were sedation and weight increase. Meta-analyses were robust and homogenous, although several of the included trials potentially suffered from high risk of bias. Unfortunately, reporting of AEs was inconsistent and limited. In conclusion, pooled analysis of data from partially outdated trials shows that 10-mg flunarizine per day is effective and well tolerated in treating episodic migraine-supporting current guideline recommendations.

Noninvasive imaging for coronary artery disease: a technology assessment for the Medicare Coverage Advisory Commission.

This report describes a review of the available scientific evidence through 2005 on direct noninvasive imaging tests (NITs) for coronary artery disease. In particular, the report addresses 6 key questions provided by the Agency for Healthcare Research and Quality and the Centers for Medicare and Medicaid Services. The questions examine the degree to which current evidence supports confident judgments about the use of NITs in the assessment of native coronary artery stenosis in clinical practice. The 2 NITs that are examined in detail in this report are 16 (and higher)-multidetector computed tomography angiography and 1.5-T magnetic resonance angiography to evaluate for stenosis in native coronary arteries. Reported sensitivity of NITs ranged from 68% to 100%; reported specificity ranged from 57% to 100% (patient-based analysis). Limitations include the exclusion of significant numbers of segments and patients, with often only the proximal coronary segments visualized. There is no direct evidence assessing the clinical use of NITs in terms of the incremental benefits or risks compared to alternative testing strategies. Although the ability of noninvasive direct coronary imaging technologies is promising-particularly the 64-multidetector computed tomography angiography-the evidence does not provide strong guidance on whether and how such technologies should be used in the population generally, or for Medicare beneficiaries specifically. Informed clinical and policy decision making will require further study of these technologies in well-characterized clinical contexts, in typical practice settings, and with attention to impact on management and health outcomes.

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

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

Methodology for lung cancer evidence review and guideline development: ACCP evidence-based clinical practice guidelines (2nd Edition).

BACKGROUND: To assemble a geographically diverse panel of experts in the diagnosis and treatment of lung cancer, representative of multiple clinical specialties, with the intention of developing clinically relevant practice guidelines for chest medicine and primary care physicians, including recommendations covering the full spectrum of care of the patient with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). METHODS: The Duke University Center for Clinical Health Policy Research was selected to review and summarize the current evidence in the treatment of NSCLC. The BlueCross BlueShield Association Technology Evaluation Center was chosen and funded by the Agency for Healthcare Research and Quality to review and synthesize the current evidence on treatment of SCLC. Other chapters received existing guidelines, systematic reviews, and metaanalyses that were published since the first edition of these guidelines, as collected by the Duke University Evidence-based Practice Center. The writing committees for these chapters conducted searches for the primary articles and additional evidence in their topic area. The expert panel established clinical recommendations founded on the synthesis of this evidence. CONCLUSIONS: This section describes the approach used to develop the guidelines, including identifying, evaluating, and synthesizing the evidence, assessing the strength of evidence and grading the individual recommendations, and suggestions for implementation of the guidelines.

Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis.

BACKGROUND: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a minimally invasive alternative technique for mediastinal staging of non-small cell lung cancer. A metaanalysis was performed to estimate the diagnostic accuracy of EUS-FNA for staging mediastinal lymph nodes (N2/N3 disease) in patients with lung cancer. METHODS: Relevant studies were identified using Medline (1966 to November 2005), CINAHL, and citation indexing. Included studies used histology or adequate clinical follow-up (> 6 months) as the "gold standard," and provided sufficient data for calculating sensitivity and specificity. Summary receiver operating characteristic curves metaanalysis was performed to estimate the pooled sensitivity and specificity. RESULTS: In 18 eligible studies, EUS-FNA identified 83% of patients (95% confidence interval [CI], 78 to 87%) with positive mediastinal lymph nodes (pooled sensitivity) and 97% of patients (95% CI, 96 to 98%) with negative mediastinal lymph nodes (pooled specificity). In eight studies that were limited to patients who had abnormal mediastinal lymph nodes seen on CT scans, the sensitivity was 90% (95% CI, 84 to 94%) and the specificity was 97% (95% CI, 95 to 98%). In patients without abnormal mediastinal lymph nodes seen on CT scans (four studies), the pooled sensitivity was 58% (95% CI, 39 to 75%). Minor complications were reported in 10 cases (0.8%). There were no major complications. CONCLUSIONS: EUS-FNA is a safe modality for the invasive staging of lung cancer that is highly sensitive when used to confirm metastasis to mediastinal lymph nodes seen on CT scans. In addition, among lung cancer patients with normal mediastinal adenopathy seen on CT scans, despite lower sensitivity, it has the potential to prevent unnecessary surgery in a large proportion of cases missed by CT scanning.