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Background: In patients with acute ischemic stroke, intracranial hemorrhages are categorized as symptomatic or asymptomatic based on the presence or absence of a clinically detectable neurological deterioration. Asymptomatic intracranial hemorrhages are believed by many to be clinically innocuous. We examined whether the occurrence of an asymptomatic intracranial hemorrhage affects functional outcome in patients with acute ischemic stroke (AIS) treated or not treated with recombinant tissue plasminogen activator (rt-PA)., Methods: We combined data from the NINDS rt-PA Stroke Trial and the ATLANTIS Trials, excluding patients with symptomatic intracranial hemorrhage (n=1193). We used generalized estimating equations to test whether asymptomatic intracranial hemorrhage altered the likelihood of a normal or near-normal outcome at 90 days, as measured across 4 commonly used functional outcome scales, controlling for other variables that affect outcome. To look at additional outcomes, including the likelihood of disability and death, we used logistic regression equations. Additionally, we systematically reviewed previous studies that assessed the effect of intracranial hemorrhage in AIS., Results: In the combined database, the rate of asymptomatic intracranial hemorrhage was higher in rt-PA treated than in nontreated patients (9.9% versus 4.2%, P<0.0001). Controlling for other prognostic factors, the odds of a normal or near-normal outcome was lower when a patient had an asymptomatic intracranial hemorrhage, but this effect did not reach statistical significance (OR=0.69, 95% CI: 0.43 to 1.12, P=0.13). Similarly, the odds of not being moderately to severely disabled (modified Rankin Score < or =2) was also lower for patients with asymptomatic intracranial hemorrhage (OR=0.60, 95% CI: 0.33 to 1.08, P=0.09). Despite using a larger sample than any previously published study, the power in our study to detect a 30% decrease in the odds of a good outcome was inadequate ( approximately 32%)., Conclusions: We could not confirm or exclude a clinically significant effect for asymptomatic intracranial hemorrhages based either on our analysis or on any previously published trial. Analysis of substantially larger databases are needed to assess the import of this common clinical event.

The innovation and diffusion of new technologies is in large measure responsible for the persistent rise in the cost of health care. The increasing cost of health care, in turn, will make cost-saving technologies more attractive. When cost-saving technologies lead to better or equivalent outcomes, their acceptance will not be controversial. However, the necessary conditions for the development and clinical acceptance of cost-saving technologies that might diminish the quality of health care have not been systematically considered. Indeed, as the clinical research enterprise has been focused almost entirely on quality-improving (or quality-neutral) innovations, new concepts may need to be introduced for quality-reducing innovations. Although the development of such therapies would, at least in some circumstances, increase overall societal benefits, replacing a standard therapy with a less effective one may conflict with deeply held values, such that conventional cost-effectiveness benchmarks might not apply. In addition, from a clinical research perspective, there are considerable ethical and methodologic hurdles that might impede the development of less expensive, less intensive therapies. In this article, using a hypothetical scenario, the authors consider economic, ethical, and research design issues concerning the innovation and diffusion of less effective, less expensive therapies and introduce 2 concepts--"decremental cost-effectiveness" and "acceptability trials"--that may in part provide a research framework for the study of "new and dis-improved" therapies.

This study determines whether prevalence and predictors of nursing home admission changed in the 1990s, during a period of dramatic changes in the service provision for and medical care of chronic impairments. Data from the 1993-2000 surveys of the Asset and Health Dynamics Among the Oldest Old (AHEAD) Study, a longitudinal and nationally representative sample, were used. Proportional hazard models were used to determine the effects of dementia, physical functioning, clinical conditions, and sociodemographics on the likelihood of nursing home admission. Of the 6,676 respondents, 17% were admitted to a nursing home. Models excluding functional impairment demonstrated significant effects of chronic medical conditions and dementia on the risk of institutionalization. After controlling for functional impairment, dementia still had significant and strong effects on institutionalization but clinical conditions did not, suggesting that the impact of dementia goes beyond its effect on physical functioning. Nursing home admissions did not decrease during the study period, and the impact of dementia on the risk of nursing home admission did not decrease. Interventions for individuals with dementia should impact the behavioral aspects of the condition and slow disease progression in addition to improving physical functioning.

The delivery of antiretroviral therapy in the developing world requires guidelines for the appropriate monitoring of therapy, including monitoring for treatment effectiveness and treatment failure, drug toxicities, adherence to therapy, and the emergence of resistant organisms. Guidelines developed in wealthy industrialized countries, which rely heavily on laboratory tests often unavailable in the developing world, may not be feasible or appropriate for resource-limited settings. Even if the standard of care routinely delivered in industrialized settings cannot be replicated, antiretroviral treatment programs with less-intense monitoring have the potential to reduce morbidity and mortality from human immunodeficiency virus. Research to identify monitoring strategies that provide the greatest benefit to those living with human immunodeficiency virus in resource-limited settings and that use the available technologies and resources needs to be conducted within a conceptual and ethical framework that takes into account differences between rich and poor countries.

To test the range of beliefs regarding the ethics of testing, in resource poor settings, new therapies that are less efficacious but more affordable and feasible than the best current therapeutic standard.

Background and Purpose: Recombinant tissue plasminogen activator (rtPA) has been demonstrated to improve outcomes in acute ischemic stroke when delivered within 3 hours of symptom onset. However, the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS B) trial, in which patients were treated mostly between 3 and 5 hours after symptom onset, found no overall benefit from rtPA. We hypothesized that a subgroup of patients at low risk for thrombolysis-related intracranial hemorrhage, identifiable on the basis of pretreatment clinical variables, may benefit even when treated after 3 hours, despite the overall results of the trial., Methods: Using an independently derived multivariate model that predicts the risk of thrombolysis-related intracranial hemorrhage in patients receiving tPA for acute myocardial infarction (based on 6 easily obtainable clinical characteristics), we stratified patients in the ATLANTIS B trial into low-, intermediate-, and high-risk tertiles. We examined outcomes in the prespecified low-risk subgroup using a global test of significance across 4 outcome scales., Results: Despite having a similar average baseline stroke severity and median time to treatment (270 minutes), patients in the prespecified low-risk group (n=194) were significantly less likely to have a symptomatic intracranial hemorrhage than other patients in the trial (2.2% versus 9.2%, P=0.03). Although there was no treatment effect for rtPA in the overall trial, a consistent trend favoring rtPA therapy (a 5% to 12% absolute treatment benefit) was found across 4 different stroke scales in the prespecified low-risk group (P=0.10). The treatment-benefit-by-risk interaction was significant (P=0.03)., Conclusions: Use of a multivariate index based on clinical variables is a promising approach to assist in the selection of patients with a favorable risk-benefit profile for thrombolytic therapy beyond 3 hours.

Objectives: To investigate whether proper patient selection might allow most of the benefits of population-wide primary coronary angioplasty to be captured in a subgroup of high-risk patients., Background: Despite growing evidence that angioplasty yields better outcomes, thrombolytic therapy remains the most common form of reperfusion therapy in acute myocardial infarction (AMI) because of limited capacity for primary coronary angioplasty at most hospitals., Methods: We used a validated logistic regression model, based on individual patient characteristics, to estimate the distribution of mortality risk in a community-based sample of 1,058 patients who received reperfusion therapy for AMI. To estimate the benefits across different baseline risks, we examined the results of 10 randomized controlled trials using meta-regression techniques., Results: Assuming a constant relative risk reduction, 68% of all mortality benefits in our community-based patient sample could be captured by treating only those patients in the highest quartile of mortality risk and 87% of the benefit could be captured by treating those in the highest half. Moreover, meta-regression of the results from the 10 clinical trials suggests that patients with a mortality risk of less than 2% may be unlikely to receive any mortality benefit. With this risk-benefit relationship, treatment of only the 39% of patients with the highest risk would yield equivalent mortality outcomes to population-wide angioplasty., Conclusion: Most of the incremental benefits of primary angioplasty can be achieved by treating high-risk patients. For these patients, thrombolytic therapy may be difficult to justify if nearby primary angioplasty is available. For most patients, however, thrombolytic therapy appears to be an effective alternative.

Background: In the Global Utilization of Streptokinase and tPA for Occluded coronary arteries (GUSTO) trial, patients with myocardial infarction who were treated with tissue plasminogen activator (tPA) had a 6.3% 30-day mortality, compared with a mortality of 7.3% among those treated with streptokinase, despite a greater risk of intracranial hemorrhage with tPA. However, in part because of its higher cost, tPA has not been adopted universally., Methods: Using an independently developed model, we predicted the benefits of tPA therapy in the 24,146 patients in the GUSTO trial and compared these predictions with the actual benefits of tPA, after classifying patients by their risks of mortality and intracranial hemorrhage. We also performed a "patient-specific" cost-effectiveness analysis among different strata of expected benefit of tPA., Results: Our model predicted that among patients with myocardial infarction, 61% of the benefit of tPA use in reducing mortality accrued to only 25% of patients; treating half of patients could capture 85% of the benefit. Including the risk of intracranial hemorrhage, our model predicted that treating half the GUSTO patients with tPA and the others with streptokinase would yield similar outcomes as treating all patients with tPA, because the additional risk of intracranial hemorrhage exceeded the expected benefit in some patients. When patients were stratified into quartiles of risk, the observed outcomes in the GUSTO patients corresponded well with these predicted results. The estimated cost-effectiveness of tPA was sensitive to patient characteristics., Conclusion: For selected patients, use of tPA yields substantially better outcomes than streptokinase, and use of the less expensive agent is difficult to justify. For many patients, however, tPA is unlikely to provide any additional benefit and, in some patients, it may even cause net harm.

Context: A meta-analysis found that primary percutaneous transluminal coronary angioplasty (PTCA) was more effective than thrombolytic therapy in reducing mortality from acute myocardial infarction. However, fewer than 20% of U.S. hospitals have facilities to perform PTCA and many clinicians must choose between immediate thrombolytic therapy and delayed PTCA., Count: The number of minutes of PTCA-related delay that would nullify its benefits., Calculation: For 10 published randomized trials, we calculated the following: PTCA-related delay = median "door-to-balloon" time--median "door-to-needle" time Survival benefit = 30-day mortality after thrombolytic therapy--30-day mortality after PTCA The relationship between delay and benefit was assessed with linear regression., Results: The reported PTCA-related delay ranged from 7 to 59 minutes, while the absolute survival benefit ranged from -2.2% (favoring thrombolytic therapy) to 7.4% (favoring PTCA). Across trials, the survival benefit decreased as the PTCA-related delay increased: For each additional 10-minute delay, the benefit was predicted to decrease 1.7% (P < 0.001). Linear regression showed that at a PTCA-related delay of 50 minutes, PTCA and thrombolytic therapy yielded equivalent reductions in mortality., Conclusions: In clinical trials with short PTCA-related delays, PTCA produced better outcomes, while trials with longer delays favored thrombolytic therapy. A more precise estimate of the time interval to equipoise between the two therapies needs to be modeled with patient-level data. At experienced cardiac centers, PTCA is probably still preferable, even with delays longer than 50 minutes.

The dramatic improvements in outcomes in acute cardiac ischemia because of therapeutic advances has led to "diminishing returns" with increasingly intensive therapies. This article explores the potential of electrocardiograph (ECG)-based prognostic instruments to identify patients likely to benefit from intense regimens, even in the absence of overall average benefit in the population, with 2 clinical examples: 1) Reperfusion therapy in acute myocardial infarction (AMI); and 2) anticoagulation/antiplatelet therapy in unstable angina. Based on previously developed, ECG-based prognostic instruments we explored the distribution of potential benefits in individual patients from increasingly intense therapy in both AMI and unstable angina. Predictions were obtained on community-based patient samples with both AMI and unstable angina to examine the distribution of effectiveness and cost-effectiveness. For both AMI and unstable angina, much of the benefit of intensifying therapy can be obtained by targeting a subgroup of patients that can be identified in multivariable dimensions by clinical and ECG characteristics. Treatment of these patients with more potent agents (such as hirudin or the glycoprotein inhibitors in unstable angina) is likely to be both effective and cost-effective. However, treatment of "low benefit" patients is unlikely to be effective or cost-effective, and some candidates for therapy are more likely to be harmed, than to benefit, by the more intensive regimens. Multivariable stratification can improve clinical and economic outcomes in acute cardiac ischemia, particularly when such models help identify "high benefit" patients early in their clinical course. Additionally, using validated models in the planning and execution of clinical trials of new therapies can improve the power of the trial and help target the therapies to patients most likely to benefit.

Randomized controlled trials (RCTs) are often considered the standard for defining the practice of evidence-based medicine. Taken alone, they are, however, often insufficient to guide clinical care. Randomized controlled trials are clearly the best method to determine whether interventions are efficacious. They have, however, numerous limitations which make them difficult to carry out or limit applicability to routine clinical practice. Although observational studies also have inherent limitations, they provide data which can help to further explain the results of randomized controlled trials. The use of observational studies to frame randomized trials can allow better application of randomized controlled trial results to individual patients and can thus help to optimize delivery of care, inform clinical practice and determine the need for further such trials.

Cancer of the paranasal sinuses and nasal cavity is an uncommon disease accounting for less than 0.2% of all malignancies. Lymphoma of the paranasal sinuses is a rare clinical entity representing less than 100 cases a year. In most cases, tumors arising in the paranasal sinuses are of the non-Hodgkin's variety. Most of these tumors are asymptomatic in the early stages and are diagnosed only after invasion of adjacent structures with local bone destruction. Computed tomography is essential for staging. The prognosis and treatment of lymphoma of the paranasal sinuses are based on the anatomic staging and histologic subtype. The prognosis is favorable for patients with localized disease. The authors describe a malignant lymphoma of the maxillary sinus in a 44-year-old man.