St John's wort for depression.

BACKGROUND: Extracts of the plant Hypericum perforatum L. (popularly called St. John's wort) have been used in folk medicine for a long time for a range of indications including depressive disorders. OBJECTIVES: To investigate whether extracts of hypericum are more effective than placebo and as effective as standard antidepressants in the treatment of depressive disorders in adults; and whether they have have less adverse effects than standard antidepressant drugs. SEARCH STRATEGY: Trials were searched in computerized databases (Cochrane Collaboration Depression, Anxiety & Neurosis Group Clinical Trials Registers; PubMed); by checking bibliographies of pertinent articles; and by contacting manufacturers and researchers. SELECTION CRITERIA: Trials were included if they: (1) were randomized and double-blind; (2) included patients with depressive disorders; (3) compared extracts of St. John's wort with placebo or standard antidepressants; and (4) included clinical outcomes such as scales assessing depressive symptoms. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, outcomes and results was extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of hypericum with placebo and standard antidepressants was the responder rate ratio (responder rate in treatment group/responder rate in control group). The main outcome measure for adverse effects was the number of patients dropping out for adverse effects. MAIN RESULTS: A total of 37 trials, including 26 comparisons with placebo and 14 comparisons with synthetic standard antidepressants, met the inclusion criteria. Results of placebo-controlled trials showed marked heterogeneity. In trials restricted to patients with major depression, the combined response rate ratio (RR) for hypericum extracts compared with placebo from six larger trials was 1.15 (95% confidence interval (CI), 1.02-1.29) and from six smaller trials was 2.06 (95% CI, 1.65 to 2.59). In trials not restricted to patients with major depression, the RR from six larger trials was 1.71 (95% CI, 1.40-2.09) and from five smaller trials was 6.13 (95% CI, 3.63 to 10.38). Trials comparing hypericum extracts and standard antidepressants were statistically homogeneous. Compared with selective serotonin reuptake inhibitors (SSRIs) and tri- or tetracyclic antidepressants, respectively, RRs were 0.98 (95% CI, 0.85-1.12; six trials) and 1.03 (95% CI, 0.93-1.14; seven trials). Patients given hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (Odds ratio (OR) 0.25; 95% CI, 0.14-0.45); such comparisons were in the same direction, but not statistically significantly different, between hypericum extracts and SSRIs (OR 0.60, 95% CI, 0.31-1.15). AUTHORS' CONCLUSIONS: Current evidence regarding hypericum extracts is inconsistent and confusing. In patients who meet criteria for major depression, several recent placebo-controlled trials suggest that the tested hypericum extracts have minimal beneficial effects while other trials suggest that hypericum and standard antidepressants have similar beneficial effects. As the preparations available on the market might vary considerably in their pharmaceutical quality, the results of this review apply only to the products tested in the included studies.

Interventions for the treatment and management of chronic fatigue syndrome: a systematic review.

CONTEXT: A variety of interventions have been used in the treatment and management of chronic fatigue syndrome (CFS). Currently, debate exists among health care professionals and patients about appropriate strategies for management. OBJECTIVE: To assess the effectiveness of all interventions that have been evaluated for use in the treatment or management of CFS in adults or children. DATA SOURCES: Nineteen specialist databases were searched from inception to either January or July 2000 for published or unpublished studies in any language. The search was updated through October 2000 using PubMed. Other sources included scanning citations, Internet searching, contacting experts, and online requests for articles. STUDY SELECTION: Controlled trials (randomized or nonrandomized) that evaluated interventions in patients diagnosed as having CFS according to any criteria were included. Study inclusion was assessed independently by 2 reviewers. Of 350 studies initially identified, 44 met inclusion criteria, including 36 randomized controlled trials and 8 controlled trials. DATA EXTRACTION: Data extraction was conducted by 1 reviewer and checked by a second. Validity assessment was carried out by 2 reviewers with disagreements resolved by consensus. A qualitative synthesis was carried out and studies were grouped according to type of intervention and outcomes assessed. DATA SYNTHESIS: The number of participants included in each trial ranged from 12 to 326, with a total of 2801 participants included in the 44 trials combined. Across the studies, 38 different outcomes were evaluated using about 130 different scales or types of measurement. Studies were grouped into 6 different categories. In the behavioral category, graded exercise therapy and cognitive behavioral therapy showed positive results and also scored highly on the validity assessment. In the immunological category, both immunoglobulin and hydrocortisone showed some limited effects but, overall, the evidence was inconclusive. There was insufficient evidence about effectiveness in the other 4 categories (pharmacological, supplements, complementary/alternative, and other interventions). CONCLUSIONS: Overall, the interventions demonstrated mixed results in terms of effectiveness. All conclusions about effectiveness should be considered together with the methodological inadequacies of the studies. Interventions which have shown promising results include cognitive behavioral therapy and graded exercise therapy. Further research into these and other treatments is required using standardized outcome measures.

Proof and policy from medical research evidence.

When judging the benefits and harms of health care and predicting patient prognosis, clinicians, researchers, and others must consider many types of evidence. Medical research evidence is part of the required knowledge base, and practitioners of evidence-based medicine must attempt to integrate the best available clinical evidence from systematic research with health professionals' expertise and patients' rights to be informed about diagnostic and therapeutic options available to them. Judging what constitutes sound evidence can be difficult because of, among other things, the sheer quantity, diversity, and complexity of medical evidence available today; the various scientific methods that have been advanced for assembling, evaluating, and interpreting such information; and the guides for applying medical research evidence to individual patients' situations. Recommendations based on sound research can then be brought forward as either guidelines or standards, and criteria exist by which valid guidelines and standards can be developed and promulgated. Nonetheless, gaps and deficiencies exist in current guidelines and in the methods for finding and synthesizing evidence. Interpreting and judging medical research involves subjective, not solely explicit, processes. Thus, developments in evidence-based medicine are an aid, but not a panacea, for definitively establishing benefits and harms of medical care, and the contributions that medical research evidence can make in any clinical or legal situation must be understood in a context in which judgment and values, understanding of probability, and tolerance for uncertainty all play a role.

Current methods of the US Preventive Services Task Force: a review of the process.

The U.S. Preventive Services Task Force (USPSTF/Task Force) represents one of several efforts to take a more evidence-based approach to the development of clinical practice guidelines. As methods have matured for assembling and reviewing evidence and for translating evidence into guidelines, so too have the methods of the USPSTF. This paper summarizes the current methods of the third USPSTF, supported by the Agency for Healthcare Research and Quality (AHRQ) and two of the AHRQ Evidence-based Practice Centers (EPCs). The Task Force limits the topics it reviews to those conditions that cause a large burden of suffering to society and that also have available a potentially effective preventive service. It focuses its reviews on the questions and evidence most critical to making a recommendation. It uses analytic frameworks to specify the linkages and key questions connecting the preventive service with health outcomes. These linkages, together with explicit inclusion criteria, guide the literature searches for admissible evidence. Once assembled, admissible evidence is reviewed at three strata: (1) the individual study, (2) the body of evidence concerning a single linkage in the analytic framework, and (3) the body of evidence concerning the entire preventive service. For each stratum, the Task Force uses explicit criteria as general guidelines to assign one of three grades of evidence: good, fair, or poor. Good or fair quality evidence for the entire preventive service must include studies of sufficient design and quality to provide an unbroken chain of evidence-supported linkages, generalizable to the general primary care population, that connect the preventive service with health outcomes. Poor evidence contains a formidable break in the evidence chain such that the connection between the preventive service and health outcomes is uncertain. For services supported by overall good or fair evidence, the Task Force uses outcomes tables to help categorize the magnitude of benefits, harms, and net benefit from implementation of the preventive service into one of four categories: substantial, moderate, small, or zero/negative. The Task Force uses its assessment of the evidence and magnitude of net benefit to make a recommendation, coded as a letter: from A (strongly recommended) to D (recommend against). It gives an I recommendation in situations in which the evidence is insufficient to determine net benefit. The third Task Force and the EPCs will continue to examine a variety of methodologic issues and document work group progress in future communications.

Screening and treating adults for lipid disorders.

CONTEXT: Screening and treatment of lipid disorders in people at high risk for future coronary heart disease (CHD) events has gained wide acceptance, especially for patients with known CHD, but the proper role in people with low to medium risk is controversial. OBJECTIVE: To examine the evidence about the benefits and harms of screening and treatment of lipid disorders in adults without known cardiovascular disease for the U.S. Preventive Services Task Force. DATA SOURCES: We identified English-language articles on drug therapy, diet and exercise therapy, and screening for lipid disorders from comprehensive searches of the MEDLINE database from 1994 through July 1999. We used published systematic reviews, hand searching of relevant articles, the second Guide to Clinical Preventive Services, and extensive peer review to identify important older articles and to ensure completeness. DATA SYNTHESIS: There is strong, direct evidence that drug therapy reduces CHD events, CHD mortality, and possibly total mortality in middle-aged men (35 to 65 years) with abnormal lipids and a potential risk of CHD events greater than 1% to 2% per year. Indirect evidence suggests that drug therapy is also effective in other adults with similar levels of risk. The evidence is insufficient about benefits and harms of treating men younger than 35 years and women younger than 45 years who have abnormal lipids but no other risk factors for heart disease and low risk for CHD events (less than 1% per year). Trials of diet therapy for primary prevention have led to long-term reductions in cholesterol of 3% to 6% but have not demonstrated a reduction in CHD events overall. Exercise programs that maintain or reduce body weight can produce short-term reductions in total cholesterol of 3% to 6%, but longer-term results in unselected populations have found smaller or no effect. To identify accurately people with abnormal lipids, at least two measurements of total cholesterol and high-density lipoprotein cholesterol are required. The role of measuring triglycerides and the optimal screening interval are unclear from the available evidence. CONCLUSIONS: On the basis of the effectiveness of treatment, the availability of accurate and reliable tests, and the likelihood of identifying people with abnormal lipids and increased CHD risk, screening appears to be effective in middle-aged and older adults and in young adults with additional cardiovascular risk factors.

Garlic shows promise for improving some cardiovascular risk factors.

OBJECTIVES: To summarize the effects of garlic on several cardiovascular-related factors and to note its adverse effects. METHODS: English and non-English citations were identified from 11 electronic databases, references, manufacturers, and experts from January 1966 through February 2000 (depending on the database searched). Reports of cardiovascular-related effects were limited to randomized controlled trials lasting at least 4 weeks. Reports of adverse effects were not limited by study design. From 1798 pertinent records, 45 randomized trials and 73 additional studies reporting adverse events were identified. Two physicians abstracted outcomes and assessed adequacy of randomization, blinding, and handling of dropouts. Standardized mean differences of lipid outcomes from placebo-controlled trials were adjusted for baseline differences and pooled using random effects methods. RESULTS: Compared with placebo, garlic preparations may lead to small reductions in the total cholesterol level at 1 month (range of average pooled reductions, 0.03-0.45 mmol/L [1.2-17.3 mg/dL]) and at 3 months (range of average pooled reductions 0.32-0.66 mmol/L [12.4-25.4 mg/dL]), but not at 6 months. Changes in low-density lipoprotein levels and triglyceride levels paralleled total cholesterol level results; no statistically significant changes in high-density lipoprotein levels were observed. Trials also reported significant reductions in platelet aggregation and mixed effects on blood pressure outcomes. No effects on glycemic-related outcomes were found. Proven adverse effects included malodorous breath and body odor. Other unproven effects included flatulence, esophageal and abdominal pain, allergic reactions, and bleeding. CONCLUSIONS: Trials suggest possible small short-term benefits of garlic on some lipid and antiplatelet factors, insignificant effects on blood pressure, and no effect on glucose levels. Conclusions regarding clinical significance are limited by the marginal quality and short duration of many trials and by the unpredictable release and inadequate definition of active constituents in study preparations.

Management of mild chronic hypertension during pregnancy: a review.

OBJECTIVE: To conduct a systematic review of evidence relating to management of mild chronic hypertension during pregnancy, including associated risks, benefits, and harms of treatment with antihypertensive agents, nonpharmacologic measures, and aspirin and benefits of various monitoring strategies. DATA SOURCES: Using four broad search strategies, we searched English and non-English-language citations in 16 electronic databases from their inception to February 1999 and consulted relevant textbooks, references, and experts. STUDY SELECTION: Reviewers screened 6228 abstracts and found 215 articles that met multiple prespecified patient selection, study population, and design criteria. TABULATION, INTEGRATION, AND RESULTS: Forty-six studies consistently showed that chronic hypertension triples the risk for perinatal mortality (odds ratio [OR] 3.4; 95% confidence interval [CI] 3.0, 3.7) and doubles the risk for placental abruption (OR 2.1; 95% CI 1.1, 3.9). Thirteen small, randomized controlled trials had inadequate power to rule in or rule out moderate-to-large (20%-50%) benefits of antihypertensive treatment. Possible adverse effects were fetal renal failure when angiotensin-converting enzyme inhibitors are used in the second or third trimester and growth restriction when atenolol is used early in pregnancy. Trials showed that aspirin neither reduces nor increases perinatal and maternal morbidity, but they did not rule out possible small-to moderate beneficial or adverse effects. No studies provide guidance on benefits or consequences of various nonpharmacologic therapies or monitoring strategies. CONCLUSION: Mild chronic hypertension is associated with increased maternal and fetal risks. Beneficial treatment and monitoring regimens are not clear, but some treatments, such as angiotensin-converting enzyme inhibitors, are best avoided.

Efficacy of newer medications for treating depression in primary care patients.

PURPOSE: Several medications have recently been introduced for the treatment of depression. We reviewed the literature to summarize their efficacy in the treatment of depression in adult patients in primary care settings. METHODS: We searched the literature published from 1980 to January 1998 using the Cochrane Collaboration Depression Anxiety and Neurosis Group's specialized registry of 8,451 clinical trials, references from trials and 46 pertinent meta-analyses, and consultation with experts. We included randomized controlled trials of at least 6 weeks' duration that measured clinical outcomes and compared one of 32 newer medications with another newer antidepressant, an older antidepressant, a placebo, or a psychosocial intervention for the treatment of depressed patients in primary care settings. The primary outcome was response rate, defined as the proportion of patients experiencing a 50% or greater improvement in depressive symptoms. RESULTS: There were 28 randomized controlled trials involving 5,940 adult primary care patients with major depression, depression requiring treatment, dysthymia, or mixed anxiety depression. Newer agents, including selective serotonin re-uptake inhibitors, serotonin norepinephrine inhibitors, reversible inhibitors of monoamine oxidase, and dopamine antagonists, were usually compared with tricyclic agents. Average response rates were 63% for newer agents, 35% for placebo, and 60% for tricyclic agents. Newer agents were significantly more effective than placebo [risk ratio = 1.6; 95% confidence interval (CI), 1.2 to 2.1), but similar to tricyclic agents (risk ratio = 1.0; 95% CI, 0.9 to 1.1). Response rates were similar in the different types of depressive disorders, except that two small trials in frail older patients showed no significant effects of newer agents compared with placebo. Dropout rates as a result of adverse effects were 8% with newer agents and 13% with tricyclic agents (P <0.05). CONCLUSIONS: In primary care settings, newer antidepressants are more effective than placebo and have similar efficacy compared with tricyclic agents in the acute treatment of depression. Dropout rates as a result of adverse effects are lower with newer compared with tricyclic agents. Future studies should compare the effectiveness of different therapies among primary care patients with less severe depression and greater medical and psychiatric comorbidity.

Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials.

OBJECTIVE: To summarise the effect of primary prevention with lipid lowering drugs on coronary heart disease events, coronary heart disease mortality, and all cause mortality. DESIGN: Meta-analysis. IDENTIFICATION: Systematic search of the Medline database from January 1994 to June 1999 for English language studies examining drug treatment for lipid disorders (use of the MeSH terms "hyperlipidemia" and "anticholesteremic agents," keyword searches for individual drug names, and a search strategy for identifying randomised trials to capture relevant articles); identification of older studies through systematic reviews and hand search of bibliographies. INCLUSION CRITERIA: All randomised trials of at least one year's duration that examined drug treatment for patients with no known coronary heart disease, cerebrovascular disease, or peripheral vascular disease and that measured clinical end points, including all cause mortality, coronary heart disease mortality, and non-fatal myocardial infarctions. DATA EXTRACTION: Review of the articles and extracted relevant data by two authors separately, with disagreements resolved by consensus. RESULTS: Four studies met eligibility criteria. Drug treatment reduced the odds of a coronary heart disease event by 30% (summary odds ratio 0.70, 95% confidence interval 0.62 to 0.79) but not the odds of all cause mortality (0.94, 0.81 to 1.09). When statin drugs were considered alone, no substantial differences in results were found. CONCLUSIONS: Treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease.

From understanding health care provider behavior to improving health care: the QUERI framework for quality improvement. Quality Enhancement Research Initiative.

Basic science and health care research provide the evidence base for the scientific practice of medicine. Over the past 2 decades, as increasingly refined tools for improving health and health care have been developed, the health care community has attempted to bridge the gap between available tools and actual health care practices. This gap can be bridged only by influencing health care provider behavior. The VA Quality Enhancement Research Initiative (QUERI) is a program designed to systematically translate research findings into better health care practices, and thus better health outcomes for enrolled veterans. Integrating provider behavior research considerations and findings into each step of the QUERI process will enhance the effectiveness of the initiative. This article presents a provider behavior research framework for planning, implementing, and evaluating quality improvement interventions within QUERI.

Pharmacotherapy for hypertension in the elderly.

OBJECTIVES: To quantify the long-term effects of antihypertensive drug therapy on morbidity and mortality in the elderly. To characterize co morbid risk profiles of trial participants. SEARCH STRATEGY: Electronic search of WHO-ISH Collaboration register (August 1997), The Cochrane Library (1997; Issue 1), MEDLINE (1966 to April 1997) and two Japanese databases (1973-1995); references from reviews, trials and 10 previously published meta-analyses; and experts. SELECTION CRITERIA: Randomized controlled trials of at least one year duration in hypertensive elders (at least 60 years old) assessing antihypertensive drug therapy and providing morbidity and mortality data. DATA COLLECTION AND ANALYSIS: At least two independent reviewers abstracted data on morbidity and mortality results and trial characteristics. The following outcomes were assessed: total mortality; coronary heart disease (CHD) mortality; combined CHD morbidity and mortality; cerebrovascular mortality; combined cerebrovascular morbidity and mortality; cardiovascular mortality; combined cardiovascular morbidity and mortality; and drop outs due to side effects of treatment. MAIN RESULTS: Fifteen trials including 21,908 elderly subjects were identified. The average prevalence of cardiovascular risk factors, cardiovascular disease, and competing co morbid diseases was lower among trial participants than the general population of hypertensive elderly persons. Most subjects were 60 to 80 years old. Most trials were conducted in Western, industrialized countries and evaluated diuretic and beta-blocker therapies. Event rates per 1000 participants over approximately 5 years indicated that antihypertensive drug therapy was beneficial. Cardiovascular morbidity and mortality was reduced from 177 to 126 events (95% CI of the difference 31 to 73). Cardiovascular mortality was reduced from 69 to 50 deaths (95% CI of the difference 9 to 31). Total mortality was reduced from 129 to 111 deaths (95% CI of difference 4 to 28). The data from the three trials restricted to persons with isolated systolic hypertension indicated a significant benefit: cardiovascular morbidity and mortality over approximately 5 years was reduced from 157 to 104 events per 1000 participants (95% CI of the difference 12 to 89). Numbers of participants who dropped out of trials secondary to adverse drug effects were often not reported. The four trials that did report this data showed a wide variation in drop out rates ranging from no significant differences between treatment and control groups to as many as one out of four patients dropping out due to side effects of treatment. REVIEWER'S CONCLUSIONS: Randomized controlled trials establish that treating healthy older persons with hypertension is highly efficacious. Benefits of treatment with low dose diuretics or beta-blockers are clear for persons in their 60s to 70s with either diastolic or systolic hypertension. Differential treatment effects based on patient risk factors, pre-existing cardiovascular disease and competing co-morbidities could not be established from the published trial data.

St John's wort for depression.

BACKGROUND: Extracts of the plant Hypericum perforatum L. (popularly called St. John's wort) have been used in folk medicine for a long time for a range of indications including depressive disorders. OBJECTIVES: To investigate whether extracts of Hypericum are more effective than placebo and as effective as standard antidepressants in the treatment of depressive disorders in adults; and whether they have have less side effects than standard antidepressant drugs. SEARCH STRATEGY: Trials were searched in computerized general (Medline, Embase, Psychlit, Psychindex) and specialized databases (Cochrane Complementary Medicine Field, Cochrane Depression & Neurosis CRG, Phytodok); by checking bibliographies of pertinent articles; and by contacting manufacturers and researchers. SELECTION CRITERIA: Trials were included if they: (1) were randomized; (2) included patients with depressive disorders; (3) compared preparations of St. John's wort (alone or in combination with other plant extracts) with placebo or other antidepressants; and (4) included clinical outcomes such as scales assessing depressive symptoms. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, outcomes and results was extracted by at least two independent reviewers using a standard form. The main outcome measure for comparing the effectiveness of Hypericum with placebo and standard antidepressants was the responder rate ratio (responder rate in treatment group/responder rate in control group). The main outcome measure for side effects was the number of patients reporting side effects. MAIN RESULTS: 27 trials including a total of 2291 patients met inclusion criteria. 17 trials with 1168 patients were placebo-controlled (16 addressed single preparations, one a combination with four other plant extracts). Ten trials (eight single preparations, two combinations of hypericum and valeriana) with 1123 patients compared hypericum with other antidepressant or sedative drugs. Most trials were four to six weeks long. Participants usually had "neurotic depression" or "mild to moderate severe depressive disorders." Hypericum preparations were significantly superior to placebo (rate ratio 2.47; 95% confidence interval 1.69 to 3.61) and similarly effective as standard antidepressants (single preparations 1.01; 0.87 to 1.16, combinations 1.52; 0.78 to 2.94). The proportions of patients reporting side effects were 26.3% for hypericum single preparations vs. 44.7% for standard antidepressants (0.57; 0.47 to 0.69), and 14. 6% for combinations vs. 26.5% with amitriptyline or desipramine (0. 49; 0.23 to 1.04). REVIEWER'S CONCLUSIONS: There is evidence that extracts of hypericum are more effective than placebo for the short-term treatment of mild to moderately severe depressive disorders. The current evidence is inadequate to establish whether hypericum is as effective as other antidepressants. Further studies comparing hypericum with standard antidepressants in well defined groups of patients over longer observations periods, investigating long term side effects, and comparing different extracts and doses are needed.