A meta-analysis of the placebo response in complementary and alternative medicine trials of irritable bowel syndrome.

Among patients with irritable bowel syndrome (IBS) enrolled in clinical trials of conventional medical therapy, the placebo response rate is high. IBS patients also frequently use complementary and alternative medicine (CAM), which may act through an 'enhanced placebo effect'. The purpose of this study was to estimate the magnitude of the placebo response rate in CAM trials for IBS and to identify factors that influence this response. We performed a systematic review and meta-analysis of randomized, placebo-controlled clinical trials of CAM therapies for IBS identified from MEDLINE/EMBASE/PsychLIT databases from 1970 to 2006. Placebo and active treatment response rates for global symptom improvement were assessed. Nineteen studies met the inclusion criteria. The pooled estimate of the placebo response rate was 42.6% (95% confidence interval, 38.0-46.5%). Significant heterogeneity existed across trials (range 15.0-72.2%, P < 0.00001). Higher placebo response rates correlated with a longer duration of treatment (r = 0.455, P = 0.05) and a greater number of office visits (r = 0.633, P = 0.03). Among IBS patients in CAM trials, the placebo response rate is high. That this rate is similar in magnitude to that seen in conventional medicine trials suggests that the placebo response is independent of the type of therapy used and that it is not particularly 'enhanced' in CAM trials.

The placebo effect in irritable bowel syndrome trials: a meta-analysis.

BACKGROUND: Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. OBJECTIVES: To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. METHODS: We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. FINDINGS: Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9-44.4). Significant associations with lower placebo response rates were fulfillment of the Rome criteria for study entry (P=0.049) and an increased number of office visits (P=0.026). CONCLUSIONS: Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

Do medical devices have enhanced placebo effects?

Although the placebo in a clinical trial is often considered simply a baseline against which to evaluate the efficacy of a clinical intervention, there is evidence that the magnitude of placebo effect may be a critical factor in determining the results of a trial. This article examines the question of whether devices have enhanced placebo effects and, if so, what the implications may be. While the evidence of an enhanced placebo effect remains rudimentary, it is provocative and therefore worthy of further study. Suggestions are made, therefore, for how such an effect can be investigated without violating the principles of informed consent.

Rehabilitative placement of poststroke patients: reliability of the Clinical Practice Guideline of the Agency for Health Care Policy and Research.

OBJECTIVE: To determine the interrater reliability of the United States Agency for Health Care Policy and Research (AHCPR) Clinical Practice Guideline Number 16 for rehabilitative placement of poststroke patients. DESIGN: Pairs of rehabilitation professionals, highly trained in the Guideline, rated the appropriateness of rehabilitative placements. SETTING: Acute care hospitals in three regions of the country. PATIENTS: Sixty patients with moderate-to-severe stroke. MEASURES: Numerous factors affecting appropriate placement according to the Guideline were abstracted from medical records or obtained by direct evaluation of patients. RESULTS: Good reliability was attained for home and nursing facility placement with rehabilitation services but with no multidisciplinary rehabilitation program (intraclass correlation coefficient = .73 and .60, respectively). Serious reliability problems were found for placements in low-intensity outpatient rehabilitation and high-intensity inpatient rehabilitation programs. Chief sources of unreliability were ambiguous or missing data in hospital medical records, complexities in the Guideline, and raters' tendencies to follow their own clinical judgments. More than one type of placement was appropriate for 65% of patients. CONCLUSIONS: Reliable placement guidelines are possible, but aspects of the Guideline require additional development. Evidence of demonstrated reliability and validity will be required to resolve disputes between rehabilitation professionals and payers regarding appropriate levels and types of rehabilitation and to guide patients and their families.

Are randomized control trial outcomes influenced by the inclusion of a placebo group?: a systematic review of nonsteroidal antiinflammatory drug trials for arthritis treatment.

Placebo groups are often included in randomized control trials evaluating drug therapy, yet we know little about the placebo effect. The purpose of our study was to evaluate how the presence of a placebo group in a randomized control trial (RCT) influences the patients' ratings of the efficacy of an active drug therapy and their reporting of its adverse effects. We identified studies published between 1966 and 1994 using MEDLINE. Randomized control trials evaluating acetylsalicylic acid, diclofenac, or indomethacin for the treatment of osteo or rheumatoid arthritis were included in our sample. Two investigators independently extracted data. Fifty-eight treatment arms met our inclusion criteria and were available for analysis. Twenty-five treatment arms evaluated a nonsteroidal antiinflammatory drug (NSAID) in placebo control trials and 33 in comparative trials. Using a logistic regression model to adjust for the differences between the evaluated drugs and between the types of arthritis, we found that patients receiving an NSAID in a placebo control trial were more likely to withdraw due to inefficacy (OR=1.3; 95% CI, 1.0 to 1.6; P=0.04). Using a similar model, withdrawals due to adverse effects were found to be more common when the NSAID was given in trials that did not include a placebo group (OR=1.5; 95% CI, 1.1 to 1.9; P=0.002) as were reports of cutaneous (OR=4.2; 95% CI, 1.7 to 9.9), gastrointestinal (OR=1.6; 95% CI, 1.3 to 2.0), and other types (OR=5.3; 95% CI, 3.8 to 7.4) of adverse effects. Although reports of central nervous system adverse effects were more frequent in the comparative trials, this difference was not significant. Including a placebo group in a RCT changes how patients rate the efficacy and adverse effects of their therapy. Our results highlight the need to consider the placebo effect in the design and analyses of clinical trials.

Safety of nifedipine in angina pectoris: a meta-analysis.

-Our objective was to compare cardiovascular event rates in patients with stable angina receiving nifedipine as monotherapy or combination therapy and in active drug controls. A MEDLARS search of published articles from 1966 to 1995 in English, French, German, Italian, or Spanish, supplemented by a manual search of bibliographies, identified 60 randomized controlled trials that met protocol criteria. Blinded articles were extracted by 2 physicians. The pooled risks of death, withdrawal, and cardiovascular event were computed and expressed as odds ratios (ORs) for all nifedipine formulations and relative to same study control drug regimens. Thirty cardiovascular events were reported in 2635 nifedipine exposures (1.14%) and 19 events in 2655 other active drug exposures (0.72%). Unadjusted ORs for nifedipine versus controls were 1.40 (95% CI, 0.56 to 3.49) for major events (death, nonfatal myocardial infarction, stroke, revascularization procedure), 1.75 (95% CI, 0.83 to 3.67) for increased angina, and 1.61 (95% CI, 0.91 to 2.87) for all events (major events plus increased angina). Episodes of increased angina were more frequent on immediate-release nifedipine (OR, 4.19 [95% CI, 1.41 to 12.49]) and on nifedipine monotherapy (OR, 2.61 [95% CI, 1.30 to 5.26]). The OR for immediate-release nifedipine was significantly higher than that for sustained-release/extended-release nifedipine (P=0.001), and the OR for nifedipine monotherapy was higher than that for nifedipine combination therapy (P=0.03). Increased risks of cardiovascular events in patients with stable angina on nifedipine were due primarily to more episodes of increased angina, confined to the immediate-release formulation and to nifedipine monotherapy.

Managing quality in hospital practice.

BACKGROUND: While routine clinical decision-making has a substantial effect on quality, most practising physicians do not routinely examine their outcomes. OBJECTIVES: To set up a practical process for identifying problems in hospital practices of primary care physicians, examine their causes, and develop a quality improvement process that intimately involves practising physicians in problem-solving. DESIGN: All hospital admissions to the Primary Care Service were screened over a 14-month period using simple pre-specified criteria. Quality problems were verified by medical record reviews carried out by two physicians. These problems were discussed at monthly meetings of physicians to characterize the problems fully, identify their causes, and document adverse effects on patient outcomes. SETTING: One community hospital. PARTICIPANTS: Primary care physicians from three group practices and four solo practices who admit patients to the Primary Care Service. INTERVENTIONS: Monthly group discussions plus discussions with individual physicians when time did not permit all quality problems to be discussed at group meetings. Certain issues of high sensitivity were also discussed with the individuals rather than in an open forum. OUTCOME MEASURES: Missed or delayed diagnoses, inappropriate treatments, and complications and their root causes. RESULTS: Quality problems were identified in 6% of all admissions. Of these, 60% were missed or delayed diagnoses, 22% were iatrogenic complications and 18% were inappropriate treatments. Root cause analysis suggested that physician behaviors led to 75% of problems; systems problems to 20% and inadequate knowledge to 5%. Process improvements included development of a call-in system to reduce delays in obtaining X-ray reports; implementation of an anticoagulation monitoring system in one group practice; and a protocol of regular feedback of errors in diagnosis to emergency room physicians. Participating physicians reported increased awareness of common errors and greater attention to detail in patient evaluations. CONCLUSIONS: Knowledge of root causes of quality problems is essential for improving quality of care. A simple routine approach to examining adverse outcomes and how care might be improved in the future was set up. Active participation of practising physicians is essential. Other organizations could use this process for routinely reviewing and improving quality.

Safety of nifedipine in patients with hypertension: a meta-analysis.

Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.

Can clinical practice guidelines increase the cost-effectiveness of geriatric rehabilitation?

The need for guidelines stems from the human and economic burdens of disabilities, from variations in practice patterns, and from controversy over the effectiveness of rehabilitation. This article describes the development of the stroke rehabilitation guidelines and highlights several recommendations that have implications for geriatric rehabilitation more generally. It then describes a pilot test of resulting review criteria and a study in progress that is examining the extent to which rehabilitation referrals after acute strokes follow guideline recommendations. Finally, it closes by underscoring several policy challenges that will be critical to achieving more cost-effective use of rehabilitation resources.

Factors contributing to practice variation in post-stroke rehabilitation.

OBJECTIVE: To analyze geographic variability in the utilization and cost of post-stroke medical care using multiple linear regression. DATA SOURCES/STUDY SETTING: A 20 percent random sample of Medicare beneficiaries with an admission to an acute care hospital for stroke during the first six months of 1991, supplemented by data from their Medicare claims and beneficiary records, the Medicare Cost Reports for hospitals and nursing homes, and the Area Resource File. STUDY DESIGN: Weighted least squares regression is used to analyze variations in post-stroke practice patterns across 151 MSAs (Metropolitan Statistical Areas). Average post-stroke costs, utilization rates, and facility lengths of stay are regressed on patient and market characteristics. DATA COLLECTION/EXTRACTION METHODS: For a six-month post-stroke interval, beneficiary-level post-stroke costs and service utilization are averaged by MSA. Variables describing market conditions are then added to these MSA-level records. PRINCIPAL FINDINGS: Patient variables rarely explain more than a third of practice variation, and often they explain substantially less than that. Market variables (with some exception) tend to be relatively less important. Finally, one-half to two-thirds of the practice variation across MSAs is unexplained by the patient and market factors measured in our data. CONCLUSIONS: A substantial portion of inter-MSA variability in utilization and intensity of post-stroke rehabilitation services cannot be explained by differences in patient characteristics. Given the large practice differences observed across MSAs, it seems unlikely that unmeasured patient differences can account for much more of the practice differences.

Poststroke rehabilitation in older Americans. The Medicare experience.

OBJECTIVES: This study examines the poststroke rehabilitation experience for a 20% sample of Medicare patients age 65 years and older admitted to an acute-care hospital with a stroke diagnosis during the 6-month interval, January 1, 1991 to June 30, 1991. Their Medicare claims data are used for two purposes: to identify current poststroke rehabilitation practice in the US population age 65 years and older, and to evaluate the importance of practice variation within this population. METHODS: Regarding the first objective, the authors develop estimates for many poststroke rehabilitation use and cost parameters that formerly were unmeasured. With respect to the second objective, the authors construct and compare average service use rates across all stroke patients in a census division and across all stroke patients residing in the 30 largest metropolitan statistical areas. RESULTS: The authors' Medicare claims analysis indicates that 73% of stroke survivors received either postacute institutional or ambulatory rehabilitation care during the first 6 months poststroke. The published stroke literature, on the other hand, focuses on the minority of stroke survivors, 16.5% in the Medicare data, who were admitted to an inpatient rehabilitation hospital. Regarding the second study objective, the Medicare analysis provides graphic evidence that poststroke rehabilitation practice varies substantially from one geographic area to another and that practice differences translate into large geographic-related differences in the cost of poststroke rehabilitation. CONCLUSIONS: The authors believe the findings demonstrate a problem with inconsistent poststroke rehabilitation practice.

Multivariate cost-effectiveness analysis: an application to optimizing ambulatory care for hypertension.

Cost-effectiveness analysis (CEA) is being used increasingly to allocate health resources efficiently. This paper develops an extension of CEA based on multivariate regression analysis and applies it to hypertension treatment. After assembling clinic and patient characteristics, outcomes, and costs for 2,439 randomly chosen patients in the 32 special hypertension clinics of the Department of Veterans Affairs (VA), we identified 19 significant predictors of cost and diastolic blood pressure (DBP) using multiple regression analysis. We classified these independent variables as "unambiguous" if a given change was associated with both lower cost and better DBP, or as "trade-off" variables if any change improving DBP entailed higher costs. The results suggest that fully implementing all unambiguous clinic changes would reduce costs by 33% while improving DBP. Multivariate CEA could help managed care companies and government programs with cost and outcome data to reduce costs and improve outcomes.

Effectiveness and costs of veterans affairs hypertension clinics.

The effectiveness and costs of care for hypertension are examined in a stratified random sample of 3,087 patients from a network of 32 Veterans Affairs Hypertension Screening and Treatment Clinics (HSTP). During 2.5 years of follow-up, 66% and 88% of patients, respectively, had mean diastolic blood pressure (DBP) levels of 90 or 95 mm Hg or less; 73% remained fully in care; and the mean cost of ambulatory care per patient-year was $647 in 1989 dollars. Higher follow-up DBP levels were found in patients who were younger, had higher DBP levels, or were receiving medication on their first visits to a clinic, were receiving more intense treatment regimens at the beginning of the follow-up period, or had been under the care of the clinic for shorter periods. Patients who were more likely to remain in care were older, received more intense treatment regimens, had prior cardiovascular complications, or had been under the care of the clinic for a longer time. Higher annual costs were associated with higher entry DBP levels, shorter durations of care, more intense regimens, and prior cardiovascular complications. Overall, patient characteristics explained 13% of the variance in mean follow-up DBP, and 31% of variance in costs. Wide variations were found among clinics in clinical outcomes and costs. After controlling for differences in patient characteristics, clinic characteristics associated with better blood pressure control were more frequent clinic visits, shorter waiting times, more time spent in patient counseling, having therapists who had a single supervisor, and better staff satisfaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgery or balloon angioplasty for peripheral vascular disease: a randomized clinical trial. Principal investigators and their Associates of Veterans Administration Cooperative Study Number 199.

PURPOSE: Surgical revascularization and angioplasty (PTA) are effective therapies for patients with peripheral arterial disease, but there are no data on long-term survival, limb salvage, and hemodynamic status from a randomized study of such patients. A multicenter, prospective trial compared PTA with bypass surgery (BP) in 263 men who had iliac, femoral, or popliteal artery obstruction. PATIENTS AND METHODS: Lesions in the iliac versus the femoropopliteal artery and rest pain versus claudication were separately randomized to the two treatment interventions. One hundred twenty-six patients underwent BP, 129 patients underwent PTA, and eight patients were not treated for lower extremity ischemia. RESULTS: Three operative deaths occurred in the BP group and none in the PTA group. For the entire study, average annual mortality was higher in the BP group, but survival was not significantly different on life-table analysis (P = .08). Primary success favored BP, while limb salvage favored PTA, but differences were not statistically significant (P = .08 and .35, respectively). Patients with iliac disease or claudication fared better, but there was no statistical difference in response to PTA or BP. CONCLUSION: Patients in both treatment groups had prompt and sustained increases in hemodynamics and quality of life. This study of patients randomly assigned to BP or PTA shows no significant difference in outcomes during a median follow-up of 4 years.

Ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension.

OBJECTIVE: To review published evidence on the use of ambulatory and self-measurement devices in the diagnosis and management of hypertension. DATA SOURCES: Computerized literature searches and manual review of bibliographies. STUDY SELECTION: Articles documenting original research pertaining to the diagnosis, treatment, or prognosis of hypertension using ambulatory or self-measurement devices. RESULTS: Studies that have compared office, self-measured, and ambulatory blood pressures have documented substantial, but nonsystematic, differences. Such findings have raised concern over the appropriateness of diagnosing hypertension and initiating drug therapy in individuals with high office blood pressure but comparatively low self-measured or ambulatory blood pressure ("office" or "white coat" hypertension). Evidence from a large number of cross-sectional studies and a single prospective study suggests that blood pressure- related end-organ damage is more closely associated with ambulatory than with office blood pressure. Less evidence supports self-measured blood pressure in this regard, and data are insufficient to compare ambulatory and self-measured blood pressure in terms of cardiovascular disease risk prediction. The estimated resource cost of an ambulatory blood pressure test is approximately $120, whereas charges range from $100 to $450. The annualized resource cost of blood pressure self-measurement is $50 or less. On a national level, the annual direct costs of ambulatory blood pressure monitoring could be as high as $6 billion, if this technique were used routinely to diagnose and monitor hypertensive patients. The extent to which direct costs would be offset by savings from less frequent or more efficient treatment for hypertension cannot be estimated reliably. Several practical and technical issues also detract from the potential usefulness of ambulatory and self-measurement devices. Finally, there is some evidence that office blood pressures measured by well-trained nonphysicians may serve as an alternative to ambulatory and self-measurement techniques in estimating usual blood pressure. CONCLUSION: Limited clinical applications of ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension appear to be warranted. Endorsement of these technologies for routine clinical use, however, will require more convincing evidence of their clinical effectiveness.

Ambulatory blood pressure monitoring. Can a clinical role be defined?

Automated ambulatory blood pressure monitoring (ABPM) is a powerful research tool, but its clinical role has been difficult to define. This paper presents conclusions on the potential clinical benefits, risks, and costs of ABPM based on a comprehensive review of the scientific literature. Support is strongest for the uses of ABPM to improve blood pressure (BP) classification in suspected hypertensives and in patients with apparent drug resistance. Four policy options are discussed. Approval for limited clinical applications appears warranted provided it is accompanied by 1) quality control standards for ABPM laboratories, 2) decision thresholds for equating office, self-monitored, and ABPM BP levels, and 3) steps to limit profit incentives and the high risk of overutilization.

Health-related quality of life among patients undergoing percutaneous transluminal coronary angioplasty.

A randomized clinical trial was recently conducted to investigate whether a new antiplatelet agent could prevent restenosis in patients who had undergone percutaneous transluminal coronary artery angioplasty (PTCA). Approximately 1,200 patients were enrolled at 13 separate clinical sites. To assess the impact of this intervention on health-related quality of life, a patient questionnaire for telephone administration was developed. This questionnaire focused attention on several specific dimensions likely to be important in this patient population: physical well-being, perceived health, emotional well-being, home management, work, recreation, and social and sexual functioning. This paper describes the instrument that was used in this trial and reports on its psychometric [corrected] properties based on completed interviews with approximately 500 patients at study entry and 1 month after PTCA.