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.

Opportunities to improve the cost-effectiveness of treatment for hypertension.

The cost-effectiveness of treatment for hypertension depends on the pretreatment level of blood pressure, age and sex of the patient, presence of other cardiovascular risk factors, long-term control of blood pressure, and the annual costs of treatment. Treatment of very mild hypertension (diastolic blood pressure, 90-94 mm Hg), even if the benefits do exceed the risks, does not appear to be particularly cost-effective. Opportunities to improve the cost-effectiveness of hypertension management lie in 1) avoidance of patient mislabeling by careful documentation of blood pressures on multiple occasions in the office and during usual activities outside the office before the diagnosis is made and treatment is begun; 2) efforts to increase adherence to scheduled visits and medication regimens; 3) attempts to step-down dosages or discontinue medications after periods of good blood pressure control; 4) explicit consideration of costs, as well as benefits, in decisions on the needed frequency of office visits, choice of medications, and use of laboratory tests; and 5) efforts to improve practice efficiency. Future practice guidelines for hypertension management should take these factors into account and should make trade-offs between benefits, risks, and costs explicit for specific types of patients.

Cost and quality trade-offs in the treatment of hypertension.

The cost-effectiveness of treatment for hypertension is positively related to the level of pretreatment blood pressure and to the level of success in achieving patient adherence to prescribed medical regimens. Opportunities to improve the cost-effectiveness of treatment include limiting treatment to patients with well-documented sustained increases in blood pressure, giving higher priority to the treatment of patients with diastolic blood pressures of 100 mm Hg and above, and relying on lower-cost medications if clinical responses to treatment permit. In patients with mild hypertension, a comparison of strategies for initiating pharmacological treatment that takes into account potential side effects as well as the costs of medications indicates a difference of $270/patient-yr between the least and most expensive alternatives. Whether the additional costs of more expensive treatment strategies are "worth it" depend on any additional health benefits actually conferred. Moreover, higher-cost strategies may have negative influences on patients' decisions to adhere to prescribed regimens or to continue in treatment. Cost is a particular problem for the treatment of chronic conditions like hypertension because of inadequate insurance coverage for medications, especially for the poor.

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.

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.

Opportunities for improving the cost-effectiveness of antihypertensive treatment.

Hypertension is an extremely important public health problem, both medically and economically. The cost burden of treatment may significantly compromise care for the individual patient, while in aggregate the direct costs of antihypertensive treatment in the United States approach $8 billion a year. Improved insurance coverage and efforts to control the costs of antihypertensive treatment are needed. Efforts to reduce the costs of care, with minimal or no reduction in its quality, should focus on the following: limiting treatment to patients with sustained diastolic hypertension; improving the efficiency of the delivery process; and emphasizing "low-cost prescribing strategies." The uncertainty that remains over the risk-benefit ratio of pharmacologic treatment for patients with very mild hypertension (90 to 94 mm Hg diastolic) raises additional questions. Even if treatment of mild hypertension is effective, it is without doubt less cost-effective than treatment of moderate and severe hypertension. Is this cost worthwhile? Such trade-offs of cost and benefits will increasingly have to be confronted in the face of limited health care resources.

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.

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.

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.

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.

Toward developing a relative value scale for medical and surgical services.

A methodology has been developed to determine the relative values of surgical procedures and medical office visits on the basis of resource costs. The time taken to perform the service and the complexity of that service are the most critical variables. Inter-specialty differences in the opportunity costs of training and overhead expenses are also considered. Results indicate some important differences between the relative values based on resource costs and existing standards, prevailing Medicare charges, and California Relative Value Study values. Most dramatic are discrepancies between existing reimbursement levels and resource cost values for office visits compared to surgical procedures. These vary from procedure to procedure and specialty to specialty but indicate that, on the average, office visits are undervalued (or surgical procedures overvalued) four- to five-fold. After standardizing the variations in the complexity of different procedures, the hourly reimbursement rate in 1978 ranged from $40 for a general practitioner to $200 for surgical specialists.

Coronary artery bypass graft surgery: clinical decision making and cost-effectiveness analysis.

Decision-analytic techniques were used to evaluate the choice between an aortocoronary bypass operation and medical management in a set of hypothetical patients with coronary artery disease. The decision framework incorporates variables believed to have an important bearing on the choice of treatment. Probability estimates were obtained from two cardiologists and one cardiac surgeon. Patient preferences for the trade-off between years of survival and the quality of life as reflected by the severity of angina pectoris were made explicit by assigning utility values to alternative health outcomes. The results are expressed in terms of quality-adjusted years of life expectancy. Decision analysis favored operation for 13 of the 14 hypothetical patients, including patients with one- and two-vessel disease. The one patient for whom medical treatment was preferred had mild angina pectoris, severe left ventricular dysfunction, and a poor prognosis regardless of therapeutic modality. The results are sensitive to changes in the probability of long-term survival, but not to changes in operative mortality rates. In five patients, the physicians' clinical judgments favored medical treatment, whereas their decision-analysis-derived estimates of survival favored operation. Possible explanations for these discrepancies are discussed. A simplified cost-effectiveness analysis for patients in whom surgery was the optimal treatment indicated costs ranging from $1,500 to $250,000 per year of life gained and from $1,500 to $32,000 per quality-adjusted year of life gained.

Packaging physician services: alternative approaches to Medicare Part B reimbursement.

More than a quarter of the rapid growth in physician expenditures since the advent of the Medicare program can be ascribed to greater service intensity, generally through unpackaging of physician services, procedure inflation, and the involvement of multiple physicians. One way to achieve effective cost control is to restrain prices and the number of services simultaneously through redefining the payment unit from a narrow procedure to a comprehensive package of services. In this paper, we explore five means of packaging physician services: collapsed procedure, office visit, special procedure, ambulatory condition, and inpatient condition packages. While three packages hold promise for reining in the costs of physician services in the Medicare program, two raise important policy considerations that would have to be addressed before they could be given further consideration.

Using physician time and complexity to identify mispriced procedures.

Physician fees have come under increasing scrutiny as policymakers attempt to constrain Medicare outlays. Our study tests the hypothesis that relative fees can be explained in terms of the physician effort involved. Our regression results show that the majority of the variation in Medicare allowed charges can be justified in terms of the physician time involved and the complexity of the procedure. Nevertheless, some surgical procedures were identified as being "overpaid" relative to their reported time and complexity, while other services appeared "underpaid," especially visits. Our methodology provides a tool for identifying "mispriced" procedures, should Congress continue its current policy of making adjustments to individual fees.

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.

Economics in hypertension management: cost and quality trade-offs.

Hypertension is a pervasive public health problem with enormous economic as well as medical consequences. Progress in developing more effective, safer and more convenient medications has been remarkable. Similarly, progress in focusing public and professional attention on hypertension has led to earlier treatment and undoubtedly contributed significantly to reduced stroke and cardiovascular mortality rates. Challenges in the next decade will be to resolve residual uncertainties about the balance of benefits and risk of treatment in mild diastolic hypertension and isolated systolic hypertension, and to develop incentives for maximizing the cost-effectiveness of treatment in those for whom treatment is, on balance, beneficial. Quality-of-life parameters will play prominent roles in clinical and policy decisions with respect to each of these challenges.