Otolaryngologist (ear, nose, throat), Plastic Surgery Specialist, Surgical Specialist
19 years of experience

Downtown Troy
Scientific Image Center #A
100 Kirts Blvd
Ste A
Troy, MI 48084
248-519-9100
Locations and availability (2)

Education ?

Medical School Score Rankings
Michigan State University (1991)
Otolaryngology
  • Currently 3 of 4 apples
Top 50%

Awards & Distinctions ?

Associations
American Academy of Cosmetic Surgery

Affiliations ?

Dr. Kent is affiliated with 1 hospitals.

Hospital Affilations

  • Botsford Generalhosp
  • Publications & Research

    Dr. Kent has contributed to 49 publications.
    Title Predicting Mortality in Incident Dialysis Patients: an Analysis of the United Kingdom Renal Registry.
    Date July 2011
    Journal American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    Excerpt

    The risk of death in dialysis patients is high, but varies significantly among patients. No prediction tool is used widely in current clinical practice. We aimed to predict long-term mortality in incident dialysis patients using easily obtainable variables.

    Title Association of Necrotizing Enterocolitis with Anemia and Packed Red Blood Cell Transfusions in Preterm Infants.
    Date June 2011
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    To determine association of anemia and red blood cell (RBC) transfusions with necrotizing enterocolitis (NEC) in preterm infants.

    Title Random Treatment Assignment Using Mathematical Equipoise for Comparative Effectiveness Trials.
    Date June 2011
    Journal Clinical and Translational Science
    Excerpt

    In controlled clinical trials, random assignment of treatment is appropriate only when there is equipoise, that is, no clear preference among treatment options. However, even when equipoise appears absent because prior trials show, on average, one treatment yields superior outcomes, random assignment still may be appropriate for some patients and circumstances. In such cases, enrollment into trials may be assisted by real-time patient-specific predictions of treatment outcomes, to determine whether there is equipoise to justify randomization. The percutaneous coronary intervention thrombolytic predictive instrument (PCI-TPI) computes probabilities of 30-day mortality for patients having ST elevation myocardial infarction (STEMI), if treated with thrombolytic therapy (TT), and if treated with PCI. We estimated uncertainty around differences in their respective predicted benefits using the estimated uncertainty of the model coefficients. Using the 2,781-patient PCI-TPI development dataset, we evaluated the distribution of predicted benefits for each patient. For three typical clinical situations, randomization was potentially warranted for 70%, 93%, and 80% of patients. Predictive models may allow real-time patient-specific determination of whether there is equipoise that justifies trial enrollment for a given patient. This approach may have utility for comparative effectiveness trials and for application of trial results to clinical practice.

    Title Assessing and Reporting Heterogeneity in Treatment Effects in Clinical Trials: a Proposal.
    Date September 2010
    Journal Trials
    Excerpt

    Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability.

    Title Elapsed Time in Emergency Medical Services for Patients with Cardiac Complaints: Are Some Patients at Greater Risk for Delay?
    Date March 2010
    Journal Circulation. Cardiovascular Quality and Outcomes
    Excerpt

    In patients with a major cardiac event, the first priority is to minimize time to treatment. For many patients, first contact with the health system is through emergency medical services (EMS). We set out to identify patient-level and neighborhood-level factors that were associated with elapsed time in EMS.

    Title Subgroup Analyses in Randomized Controlled Trials: the Need for Risk Stratification in Kidney Transplantation.
    Date November 2009
    Journal American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
    Excerpt

    Although randomized controlled trials (RCT) are the gold standard for establishing causation in clinical research, their aggregated results can be misleading when applied to individual patients. A treatment may be beneficial in some patients, but its harms may outweigh benefits in others. While conventional one-variable-at-a-time subgroup analyses have well-known limitations, multivariable risk-based analyses can help uncover clinically significant heterogeneity in treatment effects that may be otherwise obscured. Trials in kidney transplantation have yielded the finding that a reduction in acute rejection does not translate into a similar benefit in prolonging graft survival and improving graft function. This paradox might be explained by the variation in risk for acute rejection among included kidney transplant recipients varying the likelihood of benefit or harm from intense immunosuppressive regimens. Analyses that stratify patients by their immunological risk may resolve these otherwise puzzling results. Reliable risk models should be developed to investigate benefits and harms in rationally designed risk-based subgroups of patients in existing RCT data sets. These risk strata would need to be validated in future prospective clinical trials examining long-term effects on patient and graft survival. This approach may allow better individualized treatment choices for kidney transplant recipients.

    Title Much Cheaper, Almost As Good: Decrementally Cost-effective Medical Innovation.
    Date November 2009
    Journal Annals of Internal Medicine
    Excerpt

    Under conditions of constrained resources, cost-saving innovations may improve overall outcomes, even when they are slightly less effective than available options, by permitting more efficient reallocation of resources. The authors systematically reviewed all MEDLINE-cited cost-utility analyses written in English from 2002 to 2007 to identify and describe cost- and quality-decreasing medical innovations that might offer favorable "decrementally" cost-effective tradeoffs-defined as saving at least $100 000 per quality-adjusted life-year lost. Of 2128 cost-effectiveness ratios from 887 publications, only 9 comparisons (0.4% of total) described 8 innovations that were deemed to be decrementally cost-effective. Examples included percutaneous coronary intervention (instead of coronary artery bypass graft) for multivessel coronary disease, repetitive transcranial magnetic stimulation (instead of electroconvulsive therapy) for drug-resistant major depression, watchful waiting for inguinal hernias, and hemodialyzer sterilization and reuse. On a per-patient basis, these innovations yielded savings from $122 to almost $12 000 but losses of 0.001 to 0.021 quality-adjusted life-years (approximately 8 hours to 1 week). These findings demonstrate the rarity of decrementally cost-effective innovations in the medical literature.

    Title Development of Predictive Models for Airflow Obstruction in Alpha-1-antitrypsin Deficiency.
    Date October 2009
    Journal American Journal of Epidemiology
    Excerpt

    Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

    Title Are Unadjusted Analyses of Clinical Trials Inappropriately Biased Toward the Null?
    Date March 2009
    Journal Stroke; a Journal of Cerebral Circulation
    Title Stroke Prevention--insights from Incoherence.
    Date September 2008
    Journal The New England Journal of Medicine
    Title 6 Ez Steps to Improving Your Performance: (or How to Make P4p Pay 4u!).
    Date July 2008
    Journal Jama : the Journal of the American Medical Association
    Title Benchmarks and Determinants of Adherence to Stroke Performance Measures.
    Date May 2008
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Develop achievable benchmarks for 9 stroke performance measures (PM) and to identify organizational factors associated with adherence. METHODS: Adherence rates and achievable benchmarks were determined for 9 PM within a study of patients (n=2294) admitted with acute ischemic stroke at 17 hospitals. Baseline information regarding hospital characteristics and stroke-specific processes of care were collected, and multi-level models were used to test the association of these factors with adherence. RESULTS: Benchmarks were >or=90% for 8 of the 9 PM. After controlling for clustering, only use of standing orders was associated with adherence to PM, including: dysphagia screening, venous thrombosis prophylaxis, consideration of tPA, and provision of educational material. CONCLUSIONS: High levels of adherence are achievable for several acute stroke PM. Use of standing orders is associated with adherence to PM requiring immediate action on admission.

    Title Patent Foramen Ovale and Cryptogenic Stroke.
    Date April 2008
    Journal The New England Journal of Medicine
    Title A Percutaneous Coronary Intervention-thrombolytic Predictive Instrument to Assist Choosing Between Immediate Thrombolytic Therapy Versus Delayed Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction.
    Date April 2008
    Journal The American Journal of Cardiology
    Excerpt

    Based on the thrombolytic predictive instrument (TPI), we sought to create electrocardiographically based, real-time decision support to immediate identification of patients with ST-segment elevation myocardial infarction (STEMI) likely to benefit from primary percutaneous coronary intervention (PCI) compared with thrombolysis. Using data from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) Trial, we tested a mathematical model predicting mortality in patients with STEMI if treated with PCI and if treated with thrombolytic therapy. We adapted the model for incorporation into computerized electrocardiograms as a PCI-TPI. For patients with STEMI in the C-PORT Trial, the model yielded unbiased mortality predictions: for those receiving thrombolysis, it predicted 6.3% mortality and actual mortality was 6.0% (95% confidence interval 3.0 to 10.6); for those receiving PCI, it predicted 4.5% mortality and actual mortality was 3.9% (95% confidence interval 1.4 to 8.2). Excellent discrimination was reflected by its receiver operating characteristic curve area of 0.86. According to the model, and validated by actual trial outcomes, 1/3 of subjects accounted for all the mortality benefit from PCI. In conclusion, for STEMI, the PCI-TPI accurately predicts mortality for treatment with PCI and with thrombolytic therapy. Incorporated into electrocardiogram, it may assist targeting PCI to those who benefit most and identifying patients before hospitalization for whom a receiving hospital should prepare for PCI.

    Title A Geospatial Analysis of Emergency Transport and Inter-hospital Transfer in St-segment Elevation Myocardial Infarction.
    Date February 2008
    Journal The American Journal of Cardiology
    Excerpt

    Primary percutaneous coronary intervention (PCI) yields better outcomes than thrombolytic therapy in the treatment of patients with ST-segment elevation myocardial infarctions (STEMIs). Emergency medical service systems are potentially important partners in efforts to expand the use of PCI. This study was conducted to explore the probable impact on patient mortality and hospital volumes of competing strategies for the emergency transport of patients with STEMIs. Emergency transport was simulated for 2,000 patients with STEMIs from the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) trial in a geospatial model of Dallas County, Texas. Patient mortality estimates were obtained from a recently developed predictive model comparing PCI and thrombolytic therapy. A strategy of transporting patients to the closest hospital and treating with PCI if available and thrombolytic therapy if not yielded a 5.2% 30-day mortality rate (95% confidence interval [CI] 4.2% to 6.3%). A strategy of universal PCI, in which patients were transported only to PCI-capable hospitals, yielded 4.4% (95% CI 3.6% to 5.4%) mortality and an increase in patient volume at 2 full-time PCI hospitals of >1,000%. A strategy of targeted PCI, in which high-benefit patients were transported or transferred to PCI-capable hospitals, yielded 4.5% (95% CI 3.8% to 5.5%) mortality if transfers were decided in the emergency department and 4.2% (95% CI 3.4% to 5.1%) if transport was decided in the emergency vehicle. Targeted PCI strategies increased patient volumes at full-time PCI hospitals by about 700%. In conclusion, the selection of high-benefit patients for transport or transfer to PCI-capable hospitals can reduce mortality while minimizing major shifts in hospital patient volumes.

    Title Progression Risk, Urinary Protein Excretion, and Treatment Effects of Angiotensin-converting Enzyme Inhibitors in Nondiabetic Kidney Disease.
    Date December 2007
    Journal Journal of the American Society of Nephrology : Jasn
    Excerpt

    It is unclear whether patients with nondiabetic kidney disease benefit from angiotensin-converting enzyme inhibitor (ACEI) therapy when they are at low risk for disease progression or when they have low urinary protein excretion. With the use of a combined database from 11 randomized, clinical trials (n = 1860), a Cox proportional hazards model, based on known predictors of risk and the composite outcome kidney failure or creatinine doubling, was developed and used to stratify patients into equal-sized quartiles of risk. Outcome risk and treatment effect were examined across various risk strata. Use of this risk model for targeting ACEI therapy was also compared with a strategy based on urinary protein excretion alone. Control patients in the highest quartile of predicted risk had an annualized outcome rate of 28.7%, whereas control patients in the lowest quartile of predicted risk had an annualized outcome rate of 0.4%. Despite the extreme variation in risk, there was no variation in the degree of benefit of ACEI therapy (P = 0.93 for the treatment x risk interaction). Significant interaction was detected between baseline urine protein and ACEI therapy (P = 0.003). When patients were stratified according to their baseline urinary protein excretion, among the subgroup of patients with proteinuria > or =500 mg/d, significant treatment effect was seen across all patients with a measurable outcome risk, including those at relatively low risk (1.7% annualized risk for progression). However, there was no benefit of ACEI therapy among patients with proteinuria <500 mg/d, even among higher risk patients (control outcome rate 19.7%). Patients with nondiabetic kidney disease vary considerably in their risk for disease progression, but the treatment effect of ACEI does not vary across risk strata. Patients with proteinuria <500 mg/d do not seem to benefit, even when at relatively high risk for progression.

    Title Limitations of Applying Summary Results of Clinical Trials to Individual Patients: the Need for Risk Stratification.
    Date September 2007
    Journal Jama : the Journal of the American Medical Association
    Title Comparison of Mortality Benefit of Immediate Thrombolytic Therapy Versus Delayed Primary Angioplasty for Acute Myocardial Infarction.
    Date August 2007
    Journal The American Journal of Cardiology
    Excerpt

    Primary percutaneous coronary intervention (PPCI) yields superior mortality outcomes compared with thrombolysis in ST-elevation acute myocardial infarction (STEMI) but takes longer to administer. Previous meta-regressions have estimated that a procedure-related delay of 60 minutes would nullify the benefits of PPCI on mortality. Using a combined database from randomized clinical trials and registries (n = 2,781) and an independently developed model of mortality risk in STEMI, we developed logistic regression models predicting 30-day mortality for PPCI and thrombolysis by examining the influence of baseline risk on the treatment effect of PPCI and on the hazard of treatment delay. We used these models to solve mathematically for "time interval to mortality equivalence," defined as the PPCI-related delay that would nullify its expected mortality benefit over thrombolysis, and to explore the influence of baseline risk on this value. As baseline risk increases, the relative benefit of PPCI compared with thrombolytic therapy significantly increases (p = 0.002); patients with STEMI at relatively low risk of mortality accrue little or no incremental mortality benefit from PPCI, but high-risk patients benefit greatly. However, as baseline risk increases, the hazard associated with longer treatment-related delay also increases (p = 0.007). These 2 effects are compensatory and yield a roughly uniform time interval to mortality equivalence of approximately 100 minutes in patients who have at least a moderate degree of mortality risk (> approximately 4%). In conclusion, the mortality benefits of PPCI and the hazard of PPCI-related delay depend on baseline risk. Previous meta-regressions appear to have underestimated the PPCI-related delay that would nullify the incremental benefits of PPCI.

    Title Differences in Response to Reperfusion Therapies in Acute Stroke Between Men and Women: Mediated by Sex or by Chance?
    Date December 2006
    Journal Stroke; a Journal of Cerebral Circulation
    Title The Stroke-thrombolytic Predictive Instrument: a Predictive Instrument for Intravenous Thrombolysis in Acute Ischemic Stroke.
    Date December 2006
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Many patients with ischemic stroke eligible for recombinant tissue plasminogen activator (rt-PA) are not treated in part because of the risks and benefits perceived by treating physicians. Therefore, we aimed to develop a Stroke-Thrombolytic Predictive Instrument (TPI) to aid physicians considering thrombolysis for stroke. METHODS: Using data from 5 major randomized clinical trials (n=2184) testing rt-PA in the 0- to 6-hour window, we developed logistic regression equations using clinical variables as potential predictors of a good outcome (modified Rankin Scale score < or =1) and of a catastrophic outcome (modified Rankin Scale score > or =5), with and without rt-PA. The models were internally validated using bootstrap re-sampling. RESULTS: To predict good outcome, in addition to rt-PA treatment, 7 variables significantly affected prognosis and/or the treatment-effect of rt-PA: age, diabetes, stroke severity, sex, previous stroke, systolic blood pressure, and time from symptom onset. To predict catastrophic outcome, only age, stroke severity, and serum glucose were significant; rt-PA treatment was not. For patients treated within 3 hours, the median predicted probability of a good outcome with rt-PA was 42.9% (interquartile range [IQR]=18.6% to 64.7%) versus 25.3% (IQR=9.8% to 46.2%) without rt-PA; the median predicted absolute benefit was 12.5% (IQR=5.1% to 21.0%). The median probability for a catastrophic outcome, with or without, rt-PA was 15.2% (IQR=8.0% to 31.2%). The area under the receiver-operator characteristic curve was 0.788 for the model predicting good outcome and 0.775 for the model predicting bad outcome. CONCLUSIONS: The Stroke-TPI predicts good and bad functional outcomes with and without thrombolysis. Incorporated into a usable tool, it may assist in decision-making.

    Title Can Multivariable Risk-benefit Profiling Be Used to Select Treatment-favorable Patients for Thrombolysis in Stroke in the 3- to 6-hour Time Window?
    Date December 2006
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) uses multivariate equations to predict outcomes with and without thrombolysis. We sought to examine whether such a multivariate predictive instrument might be useful in selecting patients with a favorable risk-benefit treatment profile for therapy after 3 hours. METHODS: We explored outcomes in patients from 5 major randomized clinical trials testing intravenous recombinant tissue plasminogen activator (rt-PA) classified by the Stroke-TPI as "treatment-favorable" or "treatment-unfavorable." We used iterative bootstrap re-sampling to estimate how such a model would perform on independent test data. RESULTS: Among patients treated within the 3- to 6-hour window, 67% of patients were classified by Stroke-TPI predicted outcomes as "treatment-favorable" and 33% were classified as "treatment-unfavorable." Outcomes in the treatment-favorable group demonstrated benefit for thrombolysis (modified Rankin Scale score < or =1: 44.0% with rt-PA versus 34.2 with placebo, P=0.005), whereas harm was demonstrated in the treatment-unfavorable group (modified Rankin Scale score < or =1: 31.3% with rt-PA versus 38.3% with placebo; P=0.004). Bootstrap resampling with complete cross-validation showed that the absolute margin of benefit in the treatment-favorable group diminished on average by 36% between derivation and independent validation sets, but still represented a significant tripling of improvement in benefit compared with conventional inclusion criteria (5.2% [interquartile range, 1.7% to 8.6%] versus 1.8% [interquartile range, -0.5 to 4.1], P<0.0001). CONCLUSIONS: Such multivariable risk-benefit profiling may be useful in the selection of acute stroke patients for rt-PA therapy even more than 3 hours after symptom onset. Prospective testing is indicated.

    Title Implantable or External Defibrillators for Individuals at Increased Risk of Cardiac Arrest: Where Cost-effectiveness Hits Fiscal Reality.
    Date October 2006
    Journal Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research
    Excerpt

    OBJECTIVES: Implantable cardioverter defibrillators (ICDs) are highly effective at preventing cardiac arrest, but their availability is limited by high cost. Automated external defibrillators (AEDs) are likely to be less effective, but also less expensive. We used decision analysis to evaluate the clinical and economic trade-offs of AEDs, ICDs, and emergency medical services equipped with defibrillators (EMS-D) for reducing cardiac arrest mortality. METHODS: A Markov model was developed to compare the cost-effectiveness of three strategies in adults meeting entry criteria for the MADIT II Trial: strategy 1, individuals experiencing cardiac arrest are treated by EMS-D; strategy 2, individuals experiencing cardiac arrest are treated with an in-home AED; and strategy 3, individuals receive a prophylactic ICD. The model was then used to quantify the aggregate societal benefit of these three strategies under the conditions of a constrained federal budget. RESULTS: Compared with EMS-D, in-home AEDs produced a gain of 0.05 quality-adjusted life-years (QALYs) at an incremental cost of $5225 ($104,500 per QALY), while ICDs produced a gain of 0.90 QALYs at a cost of $114,660 ($127,400 per QALY). For every $1 million spent on defibrillators, 1.7 additional QALYs are produced by purchasing AEDs (9.6 QALYs/$million) instead of ICDs (7.9 QALYs/$million). Results were most sensitive to defibrillator complication rates and effectiveness, defibrillator cost, and adults' risk of cardiac arrest. CONCLUSIONS: Both AEDs and ICDs reduce cardiac arrest mortality, but AEDs are significantly less expensive and less effective. If financial constraints were to lead to rationing of defibrillators, it might be preferable to provide more people with a less effective and less expensive intervention (in-home AEDs) instead of providing fewer people with a more effective and more costly intervention (ICDs).

    Title Sex-based Differences in the Effect of Intra-arterial Treatment of Stroke: Analysis of the Proact-2 Study.
    Date September 2006
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Sex influences outcome after intravenous thrombolysis. In a combined analysis of the tissue plasminogen activator clinical trials, a sex-by-treatment interaction was observed. We sought to confirm that observation in an independent data set. METHODS: Data were from the Pro-Urokinase for Acute Cerebral Thromboembolism-2 (PROACT-2) trial. Baseline factors were compared by sex. The primary outcome was an assessment of a sex-by-treatment interaction term within a logistic regression model, using a modified Rankin Scale score <or=2 at 90 days as the binary outcome. We also assessed whether there were differences in CT-scan appearance and recanalization at 2 hours post-treatment. RESULTS: In the PROACT-2 study of intra-arterial stroke thrombolysis, in both women and men, prourokinase resulted in better outcomes than control. A sex by prourokinase treatment interaction was observed, with women showing a larger treatment effect (20% absolute benefit) compared with men (10% absolute benefit). The reason for this interaction is that thrombolytic treatment nullifies the worse outcome for untreated women compared with men. The reasons for effect modification do not include improved recanalization at 2 hours among women. CONCLUSIONS: Women with middle cerebral artery ischemic stroke benefit more from intra-arterial therapy. Further study of how sex affects stroke outcome is needed.

    Title Multivariable Risk Prediction Can Greatly Enhance the Statistical Power of Clinical Trial Subgroup Analysis.
    Date September 2006
    Journal Bmc Medical Research Methodology
    Excerpt

    BACKGROUND: When subgroup analyses of a positive clinical trial are unrevealing, such findings are commonly used to argue that the treatment's benefits apply to the entire study population; however, such analyses are often limited by poor statistical power. Multivariable risk-stratified analysis has been proposed as an important advance in investigating heterogeneity in treatment benefits, yet no one has conducted a systematic statistical examination of circumstances influencing the relative merits of this approach vs. conventional subgroup analysis. METHODS: Using simulated clinical trials in which the probability of outcomes in individual patients was stochastically determined by the presence of risk factors and the effects of treatment, we examined the relative merits of a conventional vs. a "risk-stratified" subgroup analysis under a variety of circumstances in which there is a small amount of uniformly distributed treatment-related harm. The statistical power to detect treatment-effect heterogeneity was calculated for risk-stratified and conventional subgroup analysis while varying: 1) the number, prevalence and odds ratios of individual risk factors for risk in the absence of treatment, 2) the predictiveness of the multivariable risk model (including the accuracy of its weights), 3) the degree of treatment-related harm, and 5) the average untreated risk of the study population. RESULTS: Conventional subgroup analysis (in which single patient attributes are evaluated "one-at-a-time") had at best moderate statistical power (30% to 45%) to detect variation in a treatment's net relative risk reduction resulting from treatment-related harm, even under optimal circumstances (overall statistical power of the study was good and treatment-effect heterogeneity was evaluated across a major risk factor [OR = 3]). In some instances a multi-variable risk-stratified approach also had low to moderate statistical power (especially when the multivariable risk prediction tool had low discrimination). However, a multivariable risk-stratified approach can have excellent statistical power to detect heterogeneity in net treatment benefit under a wide variety of circumstances, instances under which conventional subgroup analysis has poor statistical power. CONCLUSION: These results suggest that under many likely scenarios, a multivariable risk-stratified approach will have substantially greater statistical power than conventional subgroup analysis for detecting heterogeneity in treatment benefits and safety related to previously unidentified treatment-related harm. Subgroup analyses must always be well-justified and interpreted with care, and conventional subgroup analyses can be useful under some circumstances; however, clinical trial reporting should include a multivariable risk-stratified analysis when an adequate externally-developed risk prediction tool is available.

    Title The Potential of Training to Increase Acceptance and Use of Computerized Decision Support Systems for Medical Diagnosis.
    Date June 2006
    Journal Human Factors
    Excerpt

    OBJECTIVE: The goals of this study were to understand the reasons underlying the limited use of medical decision-support tools and to explore the potential of a computer-based tutorial to mitigate barriers to use. BACKGROUND: Medical decision-support tools such the Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) have demonstrated statistical validity and clinical impact for patient safety but have seen limited adoption and use. METHODS: The study developed a brief Web-based "demystifying" ACI-TIPI tutorial employing case-based training and evaluated the effectiveness of that tutorial in changing self-reported attitudes and behaviors. RESULTS: Clinicians using the tutorial reported greater understanding of how to use the ACI-TIPI score appropriately and increased confidence in the score. Case studies in the tutorial that provided examples of how to use the score for actual cases were rated as especially helpful. CONCLUSION: This study suggests that a primary barrier to the use of statistical decision support tools for patient diagnosis is lack of training or experience in combining a population-based numerical risk score with other diagnostic information about the individual patient's case that is not considered in that score. The results of this study indicate that there is a potential for a relatively brief tutorial to increase acceptance and use of decision support tools for medical diagnosis. APPLICATION: These findings have the potential for the identification of methods to help clinicians learn how to use statistical and probabilistic information to better assess risk and to promote integration of decision support tools into medical decision making for improvement of patient safety.

    Title Extent of Early Ischemic Changes on Computed Tomography (ct) Before Thrombolysis: Prognostic Value of the Alberta Stroke Program Early Ct Score in Ecass Ii.
    Date April 2006
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: The significance of early ischemic changes (EICs) on computed tomography (CT) to triage patients for thrombolysis has been controversial. The Alberta Stroke Program Early CT Score (ASPECTS) semiquantitatively assesses EICs within the middle cerebral artery territory using a10-point grading system. We hypothesized that dichotomized ASPECTS predicts response to intravenous thrombolysis and incidence of secondary hemorrhage within 6 hours of stroke onset. METHODS: Data from the European-Australian Acute Stroke Study (ECASS) II study were used in which 800 patients were randomized to recombinant tissue plasminogen activator (rt-PA) or placebo within 6 hours of symptom onset. We retrospectively assessed all baseline CT scans, dichotomized ASPECTS at < or =7 and >7, defined favorable outcome as modified Rankin Scale score 0 to 2 after 90 days, and secondary hemorrhage as parenchymal hematoma 1 (PH1) or PH2. We performed a multivariable logistic regression analysis and assessed for an interaction between rt-PA treatment and baseline ASPECTS score. RESULTS: We scored ASPECTS >7 in 557 and < or =7 in 231 patients. There was no treatment-by-ASPECTS interaction with dichotomized ASPECTS (P=0.3). This also applied for the 0- to 3-hour and 3- to 6-hour cohorts. However, a treatment-by-ASPECTS effect modification was seen in predicting PH (0.043 for the interaction term), indicating a much higher likelihood of thrombolytic-related parenchymal hemorrhage in those with ASPECTS < or =7. CONCLUSIONS: In ECASS II, the effect of rt-PA on functional outcome is not influenced by baseline ASPECTS. Patients with low ASPECTS have a substantially increased risk of thrombolytic-related PH.

    Title Differences in Triage Thresholds for Patients Presenting with Possible Acute Coronary Syndromes: More Than Meets the Eye.
    Date March 2006
    Journal Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research
    Excerpt

    BACKGROUND: Many studies have shown differences in cardiac care by racial/ethnic groups without accounting for institutional factors at the location of care. OBJECTIVE: Exploratory analysis of the effect of hospital funding status (public vs private) on emergency department (ED) triage decision making for patients with symptoms suggestive of acute coronary syndromes (ACSs) and on the likelihood of ED discharge for patients with confirmed ACS. STUDY DESIGN AND SETTING: Secondary analysis of data from a randomized controlled trial of 10,659 ED patients with possible ACS in five urban academic public and five private hospitals. The main outcome measures were the sensitivity and specificity of hospital admission for the presence of ACS at public and private hospitals and the adjusted odds of a patient with ACS not being hospitalized at public versus private hospitals. RESULTS: Of 10,659 ED patients, 1,856 had confirmed ACS. For patients with suspected ACS, triage decisions at private hospitals were considerably more sensitive (99 vs 96%; p<.001) but less specific (30 vs 48%; p<.001) than at public hospitals. The difference between hospital types persisted after adjustment for multiple patient-level and hospital-level characteristics. CONCLUSION: Significant differences in triage for patients with suspected ACS exist between public and private hospital EDs, even after adjustment for multiple patient demographic, clinical, and institutional factors. Further studies are needed to clarify the causes of the differences.

    Title Reporting Clinical Trial Results to Inform Providers, Payers, and Consumers.
    Date January 2006
    Journal Health Affairs (project Hope)
    Excerpt

    Results of randomized clinical trials are the preferred "evidence" for establishing the benefits and safety of medical treatments. We present evidence suggesting that the conventional approach to reporting clinical trials has fundamental flaws that can result in overlooking identifiable subgroups harmed by a treatment while underestimating benefits to others. A risk-stratified approach can dramatically reduce the chances of such errors. Since professional and economic incentives reward advocating treatments for as broad a patient population as possible, we suggest that payers and regulatory bodies might need to act to motivate prompt, routine adoption of risk-stratified assessments of medical treatments' safety and benefits.

    Title Gender Differences in Tpa-related Arterial Recanalization.
    Date December 2005
    Journal Stroke; a Journal of Cerebral Circulation
    Title "clinical-ct Mismatch" and the Response to Systemic Thrombolytic Therapy in Acute Ischemic Stroke.
    Date December 2005
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Mismatch between clinical deficits and imaging lesions in acute stroke has been proposed as a method of identifying patients who have hypoperfused but still have viable brain, and may be especially apt to respond to reperfusion therapy. We explored this hypothesis using a combined database including 4 major clinical trials of intravenous (IV) thrombolytic therapy. METHODS: To determine what the radiological correlates of a "matched" functional deficit are, we calculated the relationship between the ASPECT score of the 24-hour (follow-up) CT scan and the 24-hour National Institutes of Health Stroke Scale (NIHSS) score on the subsample with ASPECT scores performed at this time (n=820). Based on this empirical relationship, we computed the absolute difference between the observed baseline ASPECT score and the "expected" score (ie, matched) based on baseline NIHSS for all patients (n=2131). We tested whether patients with better than expected baseline ASPECTS were more likely to benefit from IV recombinant tissue plasminogen activation (rtPA). RESULTS: At 24 hours, there was a strong, linear, negative correlation between NIHSS and ASPECTS (r2=0.33, P<0.0001); on average, an increase of 10 points on NIHSS corresponded to a decrease of approximately 3 points on ASPECTS. At baseline, the average degree of mismatch between the observed and "expected" ASPECTS was 2.1 points (interquartile range, 1.0 to 3.4). However, multiple analyses failed to reveal a consistent relationship between the degree of clinical-CT mismatch at baseline and a patient's likelihood of benefiting from IV rtPA. CONCLUSIONS: Clinical-CT mismatch using ASPECT scoring does not reliably identify patients more or less likely to benefit from IV rtPA.

    Title Sex-based Differences in Response to Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke: a Pooled Analysis of Randomized Clinical Trials.
    Date August 2005
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    BACKGROUND AND PURPOSE: Women experience worse outcomes after stroke compared with men. Prior work has suggested sex-based differences in coagulation and fibrinolysis markers in subjects with acute stroke. We explored whether sex might modify the effect of recombinant tissue plasminogen activator (rtPA) on outcomes in patients with acute ischemic stroke. METHODS: Using a combined database including subjects from the National Institute of Neurological Disorders and Stroke (NINDS), Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) A and B, and the Second European Cooperative Acute Stroke Study (ECASS II) trials, we examined 90-day outcomes in patients randomized to rtPA versus placebo by sex. We used logistic regression to control for potential confounders. RESULTS: Among 988 women treated between 0 and 6 hours from symptom onset, patients receiving rtPA were significantly more likely than those receiving placebo to have a modified Rankin Score < or =1 (40.5% versus 30.3%, P<0.0008). Among 1190 men, the trend toward benefit in the overall group did not reach statistical significance (38.5% versus 36.7%, P=0.52). An unadjusted analysis showed that women were significantly more likely to benefit from rtPA compared with men (P=0.04). Controlling for age, baseline National Institutes of Health Stroke Scale, diabetes, symptom onset to treatment time, prior stroke, systolic blood pressure, extent of hypoattenuation on baseline computed tomography scan and several significant interaction terms (including onset to treatment time-by-treatment and systolic blood pressure-by treatment) did not substantially change the strength of the interaction between gender and rtPA treatment (P=0.04). CONCLUSIONS: In this pooled analysis of rtPA in acute ischemic stroke, women benefited more than men, and the usual gender difference in outcome favoring men was not observed in the thrombolytic therapy group. For patients presenting at later time intervals, when the risks and benefits of rtPA are more finely balanced, sex may be an important variable to consider for patient selection.

    Title Tissue Plasminogen Activator Was Cost-effective Compared to Streptokinase in Only Selected Patients with Acute Myocardial Infarction.
    Date December 2004
    Journal Journal of Clinical Epidemiology
    Excerpt

    OBJECTIVE: We sought to explore the patient-specific cost-effectiveness in a community-based sample for a therapy for which the average cost-effectiveness in a clinical trial has been well-described. STUDY DESIGN AND SETTING: Based on a validated multivariate model, we generated predictions of the effectiveness and cost-effectiveness of t-PA compared to streptokinase on 921 consecutive patients who received thrombolytic therapy for acute myocardial infarction. RESULTS: The average cost-effectiveness of t-PA was US dollar 40,140 per life-year saved. For the quartile of patients most likely to benefit, the incremental cost-effectiveness of t-PA was US dollar 15,396. However, only 44% of patients who received thrombolytic therapy had an estimated cost-effectiveness ratio below US dollar 50,000 per year of life saved; the ratio was greater than US dollar 100,000 in 37% of treated patients. Patients in the lowest quartile of expected benefit are, overall, more likely to be harmed than to benefit from t-PA. CONCLUSION: Compared to the pattern of thrombolytic agent choice observed, targeting t-PA to the half of patients most likely to benefit could save 247 lives and US dollar 174 million nationally per year.

    Title Predicting Nursing Home Admission: Estimates from a 7-year Follow-up of a Nationally Representative Sample of Older Americans.
    Date September 2004
    Journal Alzheimer Disease and Associated Disorders
    Excerpt

    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.

    Title New and Dis-improved: on the Evaluation and Use of Less Effective, Less Expensive Medical Interventions.
    Date August 2004
    Journal Medical Decision Making : an International Journal of the Society for Medical Decision Making
    Excerpt

    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.

    Title In Acute Ischemic Stroke, Are Asymptomatic Intracranial Hemorrhages Clinically Innocuous?
    Date May 2004
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    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.

    Title Testing Therapies Less Effective Than the Best Current Standard: Ethical Beliefs in an International Sample of Researchers.
    Date November 2003
    Journal The American Journal of Bioethics : Ajob
    Excerpt

    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.

    Title Is Primary Angioplasty for Some As Good As Primary Angioplasty for All?
    Date June 2003
    Journal Journal of General Internal Medicine : Official Journal of the Society for Research and Education in Primary Care Internal Medicine
    Excerpt

    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.

    Title Are Some Patients Likely to Benefit from Recombinant Tissue-type Plasminogen Activator for Acute Ischemic Stroke Even Beyond 3 Hours from Symptom Onset?
    Date March 2003
    Journal Stroke; a Journal of Cerebral Circulation
    Excerpt

    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.

    Title Primary Angioplasty or Thrombolysis for Acute Myocardial Infarction?
    Date January 2003
    Journal Lancet
    Title An Independently Derived and Validated Predictive Model for Selecting Patients with Myocardial Infarction Who Are Likely to Benefit from Tissue Plasminogen Activator Compared with Streptokinase.
    Date August 2002
    Journal The American Journal of Medicine
    Excerpt

    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.

    Title Balancing the Benefits of Primary Angioplasty Against the Benefits of Thrombolytic Therapy for Acute Myocardial Infarction: the Importance of Timing.
    Date December 2001
    Journal Effective Clinical Practice : Ecp
    Excerpt

    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.

    Title The Potential Use of Ecg-based Prognostic Instruments in Clinical Trials and Cost-effectiveness Analyses of New Therapies in Acute Cardiac Ischemia.
    Date April 2001
    Journal Journal of Electrocardiology
    Excerpt

    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.

    Title Are Randomized Controlled Trials Sufficient Evidence to Guide Clinical Practice in Type Ii (non-insulin-dependent) Diabetes Mellitus?
    Date March 2000
    Journal Diabetologia
    Excerpt

    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.

    Title The Gender Effect in Stroke Thrombolysis: of Cases, Controls, and Treatment-effect Modification.
    Date
    Journal Neurology
    Excerpt

    BACKGROUND: Large studies of patients with acute stroke not receiving thrombolytic therapy have repeatedly demonstrated poorer outcomes for women compared to men. An analysis of five pooled randomized controlled trials testing IV recombinant tissue plasminogen activator (rtPA) demonstrated that rtPA benefits women more than men; the usual gender difference, apparent among controls, was totally nullified in the rtPA group. This nullification of the usual gender effect among rtPA-treated patients has not been confirmed. METHODS: We analyzed baseline characteristics and functional outcomes in men vs women in the Canadian Alteplase for Stroke Effectiveness Study (CASES), a multicenter study that collected outcomes data for patients treated with rtPA in Canada to assess the safety and effectiveness of alteplase for stroke in the context of routine care. RESULTS: Among 1,110 patients, including 615 men and 505 women, a normal or near normal outcome at 90 days was found in 37.1% of men vs 36.0% of women (p = 0.71). This was essentially unchanged after adjusting for differences in baseline characteristics, including age >70, glucose, hypertension, atrial fibrillation, hypercholesterolemia, baseline National Institute of Health Stroke Severity, and baseline Alberta Stroke Program Early CT score (35.2% in men vs 38.2% in women, p = 0.332). Ninety-day mortality was similar between the sexes in both the adjusted and unadjusted analysis. CONCLUSIONS: There was no difference in 90-day outcomes in recombinant tissue plasminogen activator (rtPA)-treated men and rtPA-treated women. This is consistent with the pooled analysis of randomized controlled trials, showing greater benefit for thrombolysis in women and nullification of the usual gender difference in outcome.

    Title Competing Risk and Heterogeneity of Treatment Effect in Clinical Trials.
    Date
    Journal Trials
    Excerpt

    ABSTRACT: It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks - which may or may not be correlated - may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend.

    Title Association of Prolonged Qrs Duration with Ventricular Tachyarrhythmias and Sudden Cardiac Death in the Multicenter Automatic Defibrillator Implantation Trial Ii (madit-ii).
    Date
    Journal Heart Rhythm : the Official Journal of the Heart Rhythm Society
    Excerpt

    BACKGROUND: There is conflicting literature on the relationship between prolonged QRS duration (QRSd) and arrhythmic events, including sudden cardiac death (SCD), in heart failure patients with or without implantable cardioverter-defibrillators (ICDs). OBJECTIVE: The purpose of this study was to evaluate the prognostic significance of prolonged QRSd relative to arrhythmic outcomes in medically and ICD-treated patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. METHODS: Using a Cox proportional hazards model adjusting for ejection fraction, heart failure class, and blood urea nitrogen, we estimated the association of prolonged QRSd >/=140 ms with SCD in the medically treated arm and SCD or first appropriate ICD therapy for rapid ventricular tachycardia/fibrillation (VT/VF; cycle length </=260 ms) in the ICD-treated arm. RESULTS: In the medically treated arm, prolonged QRSd was a significant independent predictor of SCD (hazard ratio 2.12; 95% confidence interval 1.20-3.76; P = .01). However, in the ICD-treated arm, prolonged QRSd did not predict SCD or rapid VT/VF (hazard ratio 0.77; 95% CI 0.47-1.24; P = .28). The difference in the prognostic effect of prolonged QRSd in these two groups was significant (P<.01). These results were not affected by varying the cycle length that defines rapid VT/VF or the duration that defines QRSd prolongation. CONCLUSIONS: In patients with prior myocardial infarction and EF </=30%, prolonged QRSd does not predict SCD/VT/VF in ICD-treated patients but does predict SCD in medically treated patients. This underscores the nonequivalence of VT/VF and SCD and the need for caution in inferring risk of SCD when using nonrandomized databases that include only patients with ICDs.

    Title Statins, Low-density Lipoprotein Cholesterol, and Risk of Cancer.
    Date
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES: We sought to assess whether statin-mediated reductions in low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of cancer. BACKGROUND: We recently reported an inverse association between on-treatment LDL-C levels and incident cancer in statin-treated patients enrolled in large randomized controlled trials, raising concern that LDL-C lowering by statins may increase cancer risk. However, meta-analyses suggest a neutral overall effect of statins on incident cancer. METHODS: A systematic literature search identified 15 eligible randomized controlled trials of statins with >or=1,000 person-years of follow-up that provided on-treatment LDL-C levels and rates of incident cancers (19 statin and 14 control arms, 437,017 person-years cumulative follow-up, and 5,752 incident cancers). RESULTS: In the statin arms, meta-regression analysis demonstrated an inverse association between on-treatment LDL-C and incident cancer, with an excess of 2.2 (95% confidence interval: 0.7 to 3.6) cancers per 1,000 person-years for every 10 mg/dl decrement in on-treatment LDL-C (p=0.006). The corresponding difference among control arms was 1.2 (95% confidence interval: -0.2 to 2.7, p=0.09). Compared with the control arms, the statin regression line was significantly shifted leftward, such that similar rates of incident cancer were associated with lower on-treatment LDL-C (p<0.05). Meta-regression demonstrated that statins lack an effect on cancer risk across all levels of on-treatment LDL-C. CONCLUSIONS: There is an inverse association between on-treatment LDL-C and incident cancer. However, statins, despite producing marked reductions in LDL-C, are not associated with an increased risk of cancer.

    Title Comparative Effectiveness of St-segment-elevation Myocardial Infarction Regionalization Strategies.
    Date
    Journal Circulation. Cardiovascular Quality and Outcomes
    Excerpt

    Primary percutaneous coronary intervention (PCI) is more effective on average than fibrinolytic therapy in the treatment of ST-segment-elevation myocardial infarction. Yet, most US hospitals are not equipped for PCI, and fibrinolytic therapy is still widely used. This study evaluated the comparative effectiveness of ST-segment-elevation myocardial infarction regionalization strategies to increase the use of PCI against standard emergency transport and care.

    Title The Surgical Apgar Score in Hip and Knee Arthroplasty.
    Date
    Journal Clinical Orthopaedics and Related Research
    Excerpt

    A 10-point Surgical Apgar Score, based on patients' estimated blood loss, lowest heart rate, and lowest mean arterial pressure during surgery, was developed to rate patients' outcomes in general and vascular surgery but has not been tested for patients having orthopaedic surgery.


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