Proceedings of the first academic symposium on developing, qualifying and operating a cell and gene therapy manufacturing facility.

A significant portion of the more than 1000 candidate cell and gene therapy products currently under clinical investigation (clinicaltrials.gov) are born out of academic research centers affiliated with universities, hospitals and non-profit research institutions. Supporting these efforts are myriad academic clinical materials production facilities with more than 40 such facilities currently operational in the United States alone. In March 2018, Stanford University's Laboratory for Cell and Gene Therapy held a symposium with the leaders and staff of more than 25 similar facilities to discuss the collective experience in developing, qualifying and operating cell and gene therapy manufacturing facilities according to current Good Manufacturing Practices. Topics included facility design, construction, staffing and operations and compliance. Leaders from several institutions gave overviews of the history of development of the facilities and discussed challenges and opportunities they had experienced over the past 10-20 years of operations. Working sessions were also held to discuss specific aspects of Process Development, Manufacturing, Quality Systems, Regulatory Affairs and Business Development with all participants contributing to the discussions. We summarize here the findings of this inaugural meeting with an emphasis on best practices and suggested guidelines for operations.

Relationship of Hospital Staff Coverage and Delivery Room Resuscitation Practices to Birth Asphyxia.

Objective The objective of this study was to assess utilization of specialist coverage and checklists in perinatal settings and to examine utilization by birth asphyxia rates. Design This is a survey study of California maternity hospitals concerning checklist use to prepare for delivery room resuscitation and 24-hour in-house specialist coverage (pediatrician/neonatologist, obstetrician, and obstetric anesthesiologist) and results linked to hospital birth asphyxia rates (preterm and low weight births were excluded). Results Of 253 maternity hospitals, 138 responded (55%); 59 (43%) indicated checklist use, and in-house specialist coverage ranged from 38% (pediatrician/neonatologist) to 54% (anesthesiology). In-house coverage was more common in urban versus rural hospitals for all specialties (p < 0.0001), but checklist use was not significantly different (p = 0.88). Higher birth volume hospitals had more specialist coverage (p < 0.0001), whereas checklist use did not differ (p = 0.3). In-house obstetric coverage was associated with lower asphyxia rates (odds ratio: 0.34; 95% confidence interval [CI]: 0.20, 0.58) in a regression model accounting for other providers. Checklist use was not associated with birth asphyxia (odds ratio: 1.12; 95% CI: 0.75, 1.68). Conclusion Higher birth volume and urban hospitals demonstrated greater in-house specialist coverage, but checklist use was similar across all hospitals. Current data suggest that in-house obstetric coverage has greater impact on asphyxia than other specialist coverage or checklist use.

Severe maternal morbidity in a large cohort of women with acute severe intrapartum hypertension.

BACKGROUND: Hypertensive diseases of pregnancy are associated with severe maternal morbidity and remain common causes of maternal death. Recently, national guidelines have become available to aid in recognition and management of hypertension in pregnancy to reduce morbidity and mortality. The increased morbidity related to hypertensive disorders of pregnancy is presumed to be associated with the development of severe hypertension. However, there are few data on specific treatment or severe maternal morbidity in women with acute severe intrapartum hypertension as opposed to severe preeclampsia. OBJECTIVE: The study aimed to characterize maternal morbidity associated with women with acute severe intrapartum hypertension, and to determine whether there was an association between various first-line antihypertensive agents and posttreatment blood pressure. STUDY DESIGN: This retrospective cohort study of women delivering between July 2012 and August 2014 at 15 hospitals participating in the California Maternal Quality Care Collaborative compared women with severe intrapartum hypertension (systolic blood pressure >160 mm Hg or diastolic blood pressure >105 mm Hg) to women without severe hypertension. Hospital Patient Discharge Data and State of California Birth Certificate Data were used. Severe maternal morbidity using the Centers for Disease Control and Prevention criteria based on International Classification of Diseases-9 codes was compared between groups. The efficacy of different antihypertensive medications in meeting the 1-hour posttreatment goal was determined. Statistical methods included distribution appropriate univariate analyses and multivariate logistic regression. RESULTS: There were 2252 women with acute severe intrapartum hypertension and 93,650 women without severe hypertension. Severe maternal morbidity was significantly more frequent in the women with severe hypertension (8.8%) compared to the control women (2.3%) (P < .0001). Severe maternal morbidity rates did not increase with increasing severity of blood pressures (P = .90 for systolic and .42 for diastolic). There was no difference in severe maternal morbidity between women treated (8.6%) and women not treated (9.5%) (P = .56). Antihypertensive treatment rates were significantly higher in hospitals with a level IV neonatal intensive care unit (85.8%) compared to a level III neonatal intensive care unit (80.2%) (P < .001), and in higher-volume hospitals (84.5%) compared to lower-volume hospitals (69.1%) (P < .001). Severe maternal morbidity rates among severely hypertensive women were significantly higher in hospitals with level III neonatal intensive care unit level compared to hospitals with a level IV neonatal intensive care unit (10.6% vs 5.7%, respectively; P < .001), and significantly higher in low-delivery volume hospitals compared to high-delivery volume hospitals (15.5% vs 7.6%, respectively; P < .001). Only 53% of women treated with oral labetalol as first-line medication met the posttreatment goal of nonsevere hypertension, significantly less than those treated with intravenous hydralazine, intravenous labetalol, or oral nifedipine (68%, 71%, and 82%, respectively) (P = .001). Severe intrapartum hypertension remained untreated in 17% of women. CONCLUSION: Women with acute severe intrapartum hypertension had a significantly higher risk of severe maternal morbidity compared to women without severe hypertension. Significantly lower antihypertensive treatment rates and higher severe maternal morbidity rates were seen in lower-delivery volume hospitals.

Measuring severe maternal morbidity: validation of potential measures.

BACKGROUND: Both maternal mortality rate and severe maternal morbidity rate have risen significantly in the United Sates. Recently, the Centers for Disease Control and Prevention introduced International Classification of Diseases, 9th revision, criteria for defining severe maternal morbidity with the use of administrative data sources; however, those criteria have not been validated with the use of chart reviews. OBJECTIVE: The primary aim of the current study was to validate the Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria for the identification of severe maternal morbidity. This analysis initially required the development of a reproducible set of clinical conditions that were judged to be consistent with severe maternal morbidity to be used as the clinical gold standard for validation. Alternative criteria for severe maternal morbidity were also examined. STUDY DESIGN: The 67,468 deliveries that occurred during a 12-month period from 16 participating California hospitals were screened initially for severe maternal morbidity with the presence of any of 4 criteria: (1) Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, diagnosis and procedure codes; (2) prolonged postpartum length of stay (>3 standard deviations beyond the mean length of stay for the California population); (3) any maternal intensive care unit admissions (with the use of hospital billing sources); and (4) the administration of any blood product (with the use of transfusion service data). Complete medical records for all screen-positive cases were examined to determine whether they satisfied the criteria for the clinical gold standard (determined by 4 rounds of a modified Delphi technique). Descriptive and statistical analyses that included area under the receiver operating characteristic curve and C-statistic were performed. RESULTS: The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria had a reasonably high sensitivity of 0.77 and a positive predictive value of 0.44 with a C-statistic of 0.87. The most important source of false-positive cases were mothers whose only criterion was 1-2 units of blood products. The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria screen rate ranged from 0.51-2.45% among hospitals. True positive severe maternal morbidity ranged from 0.05-1.13%. When hospitals were grouped by their neonatal intensive care unit level of care, severe maternal morbidity rates were statistically lower at facilities with lower level neonatal intensive care units (P < .0001). CONCLUSION: The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria can serve as a reasonable administrative metric for measuring severe maternal morbidity at population levels. Caution should be used with the use of these criteria for individual hospitals, because case-mix effects appear to be strong.

Pregnancy outcomes in the super obese, stratified by weight gain above and below institute of medicine guidelines.

OBJECTIVE: To examine the association of antenatal weight gain above and below the 2009 Institute of Medicine (IOM) guidelines in the super-obese population (body mass index [BMI] of 50 or higher) on the maternal and neonatal morbidities of gestational hypertension or preeclampsia (pregnancy-induced hypertension), gestational diabetes mellitus, cesarean delivery, birth weight more than 4,000 g and more than 4,500 g, low birth weight, and preterm birth. METHODS: The effect of gestational weight gain was assessed in this retrospective cohort study using California birth certificate and patient discharge diagnosis data. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) as a function of antenatal weight gain. Weight gain within 2009 IOM guidelines (11-20 pounds) served as the reference group. RESULTS: The study population consisted of 1,034 women. Women gaining below, within, and above IOM guidelines accounted for 38.3, 23.5, and 38.2%, respectively. Weight gain below IOM guidelines was not associated with a statistically increased odds of preterm birth (OR 1.82, 95% CI 0.60-5.59) or low birth weight (OR 1.20, 95% CI 0.57-2.49); however, birth weight more than 4,000 g was significantly reduced (OR 0.50, 95% CI 0.32-0.77). Excessive weight gain statistically increased the odds of pregnancy-induced hypertension (OR 1.96, 95% CI 1.26-3.03) and cesarean delivery (OR 1.40, 95% CI 1.00-1.97) while not appearing to protect against the delivery of low-birth-weight neonates (OR 0.84, 95% CI 0.40-1.78). CONCLUSION: Weight gain below the current guidelines in the super-obese cohort is not associated with an increase in maternal or neonatal risk while decreasing the odds of delivering a macrosomic neonate. Women with BMIs of 50 or higher may warrant separate gestational weight gain recommendations.

The impact of change in pregnancy body mass index on macrosomia.

OBJECTIVE: To examine the impact of change in body mass index (BMI) during pregnancy on the incidence of macrosomia. METHODS: This is a retrospective cohort study using 2007 linked birth certificate and discharge diagnosis data from the state of California. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated for the outcome of macrosomia, as a function of a categorical change in pregnancy BMI: BMI loss (<-0.5), no change (-0.5 to 0.5), minimal (0.6 to 5), moderate (5.1 to 10), and excessive (>10). The impact of pregnancy change in BMI was determined for the entire cohort and then stratified by prepregnancy BMI category. Minimal BMI change served as the reference group. RESULTS: The study population consisted of 436,414 women. Overall, women with moderate and excessive BMI changes had aORs of 1.66 and 3.21, respectively, for macrosomia, when compared with women with minimal BMI change. When stratified by prepregnancy BMI, normal (aOR 3.85) and overweight women (aOR 2.96) with antenatal BMI change greater than 10 had the highest odds of macrosomia. CONCLUSIONS: Excessive change in pregnancy BMI results in an increased odds of macrosomia. This finding was most pronounced in the normal and overweight women.

Maternal prepregnancy body mass index and risk of spontaneous preterm birth.

BACKGROUND: Findings from studies examining risk of preterm birth associated with elevated prepregnancy body mass index (BMI) have been inconsistent. METHODS: Within a large population-based cohort, we explored associations between prepregnancy BMI and spontaneous preterm birth across a spectrum of BMI, gestational age, and racial/ethnic categories. We analysed data for 989,687 singleton births in California, 2007-09. Preterm birth was grouped as 20-23, 24-27, 28-31, or 32-36 weeks gestation (compared with 37-41 weeks). BMI was categorised as <18.5 (underweight); 18.5-24.9 (normal); 25.0-29.9 (overweight); 30.0-34.9 (obese I); 35.0-39.9 (obese II); and ≥ 40.0 (obese III). We assessed associations between BMI and spontaneous preterm birth of varying severity among non-Hispanic White, Hispanic, and non-Hispanic Black women. RESULTS: Analyses of mothers without hypertension and diabetes, adjusted for age, education, height, and prenatal care initiation, showed obesity categories I-III to be associated with increased risk of spontaneous preterm birth at 20-23 and 24-27 weeks among those of parity 1 in each race/ethnic group. Relative risks for obese III and preterm birth at 20-23 weeks were 6.29 [95% confidence interval (CI) 3.06, 12.9], 4.34 [95% CI 2.30, 8.16], and 4.45 [95% CI 2.53, 7.82] for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, respectively. A similar, but lower risk, pattern was observed for women of parity ≥ 2 and preterm birth at 20-23 weeks. Underweight was associated with modest risks for preterm birth at ≥ 24 weeks among women in each racial/ethnic group regardless of parity. CONCLUSIONS: The association between women's prepregnancy BMI and risk of spontaneous preterm birth is complex and is influenced by race/ethnicity, gestational age, and parity.

The impact of change in pregnancy body mass index on cesarean delivery.

OBJECTIVE: To examine the impact of pregnancy changes in body mass index (BMI) on the incidence of cesarean delivery. METHODS: This is a retrospective cohort study using linked birth certificate and discharge diagnosis data from the year 2007. Adjusted odds ratios (aOR) were calculated for the outcome of cesarean delivery, as a function of a categorical change in pregnancy BMI (kg/m(2)): BMI loss (BMI change<-0.5), no change (-0.5 to 0.5), minimal (0.6 to 5), moderate (5.1 to 10) and excessive (>10). The impact of pregnancy change in BMI was determined for the entire cohort and then stratified by prepregnancy BMI category. RESULTS: The study population consisted of 436 414 women with singleton gestations. When compared to women with no net change in BMI, women with excessive BMI changes collectively had a 80% increased incidence of cesarean delivery (aOR = 1.78). By prepregnancy obesity class, the aOR for cesarean delivery in women with excessive BMI change were: normal weight (aOR = 2.25), overweight (aOR = 2.39), obese class I (aOR = 2.23), obese class II (aOR = 2.56) and obese class III (aOR = 2.08). CONCLUSIONS: The odds of cesarean delivery were uniformly increased in all prepregnancy BMI categories as net BMI change increased. These data illustrate that all women, not just the overweight and obese, are at significantly increased risk of cesarean delivery with excessive BMI change during pregnancy.

Creating a public agenda for maternity safety and quality in cesarean delivery.

Cesarean delivery rates in California and the United States rose by 50% between 1998 and 2008 and vary widely among states, regions, hospitals, and health care providers. The leading driver of both the rise and the variation is first-birth cesarean deliveries performed during labor. With the large increase in primary cesarean deliveries, repeat cesarean delivery now has emerged as the largest single indication. The economic costs, health risks, and negligible benefits for most mothers and newborns of these higher rates point to the urgent need for a new approach to working with women in labor. This commentary analyzes the high rates and wide variations and presents evidence of costs and risks associated with cesarean deliveries (complete discussion provided in the California Maternal Quality Care Collaborative White Paper at www.cmqcc.org/white_paper). All stakeholders need to ask whether society can afford the costs and complications of this high cesarean delivery rate and whether they can work together toward solutions. The factors involved in the rise in cesarean deliveries point to the need for a multistrategy approach, because no single strategy is likely to be effective or lead to sustained change. We outline complementary strategies for reducing the rates and offer recommendations including clinical improvement strategies with careful examination of labor management practices; payment reform to eliminate negative or perverse incentives; education to recognize the value of vaginal birth; and full transparency through public reporting and continued public engagement.

Increasing pre-pregnancy body mass index is predictive of a progressive escalation in adverse pregnancy outcomes.

OBJECTIVE: To evaluate the association between pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes using a large administrative database. METHODS: Retrospective cohort study of California women delivering singletons in 2007. The association between pre-pregnancy BMI category and adverse outcomes were evaluated using multivariate logistic regression. RESULTS: Among 436,414 women, increasing BMI was associated with increasing odds of adverse outcomes. Obese women (BMI=30-39.9) were nearly 3 x more likely to have gestational diabetes (OR=2.83, 95% CI=2.74-2.92) and gestational hypertension/preeclampsia (2.68, 2.59-2.77) and nearly twice as likely to undergo cesarean (1.82, 1.78-1.87), when compared to normal BMI women (BMI=18.5-24.9). Morbidly obese women (BMI ≥ 40) were 4x more likely to have gestational diabetes (4.72, 4.46-4.99) and gestational hypertension/preeclampsia (4.22, 3.97-4.49) and nearly 3 x as likely to undergo cesarean (2.60, 2.46-2.74). CONCLUSION: There is a strong association between increasing maternal BMI and adverse pregnancy outcomes. This information is important for counseling women regarding the risks of obesity in pregnancy.

Health status after treatment for coronary artery disease and type 2 diabetes mellitus in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

BACKGROUND: Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly. METHODS AND RESULTS: Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized 2368 patients with type 2 diabetes mellitus and stable ischemic heart disease to (1) prompt revascularization versus medical therapy and (2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery or percutaneous coronary intervention. The Duke Activity Status Index and RAND Energy, Health Distress, and Self-Rated Health scales were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to 1 year (P<0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in Duke Activity Status Index (1.32 points; P<0.001), Energy (1.36 points; P=0.02), and Self-rated Health (1.77 points; P=0.007) but not Health Distress (-0.47; P=0.46). These treatment effects were largely maintained over 4 years of follow-up. The effect of revascularization on the Duke Activity Status Index was significantly larger in the subgroup of patients intended for coronary artery bypass graft surgery compared with the subgroup intended for percutaneous coronary intervention. Health status did not differ significantly on any of the 4 measures between the insulin provision and insulin sensitization strategies. CONCLUSIONS: Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes mellitus and stable ischemic heart disease. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Nutritional factors that influence change in bone density and stress fracture risk among young female cross-country runners.

OBJECTIVE: To identify nutrients, foods, and dietary patterns associated with stress fracture risk and changes in bone density among young female distance runners. DESIGN AND SETTING: Two-year, prospective cohort study. Observational data were collected in the course of a multicenter randomized trial of the effect of oral contraceptives on bone health. PARTICIPANTS: One hundred and twenty-five female competitive distance runners ages 18-26 years. ASSESSMENT OF RISK FACTORS: Dietary variables were assessed with a food frequency questionnaire. MAIN OUTCOME MEASUREMENTS: Bone mineral density and content (BMD/BMC) of the spine, hip, and total body were measured annually by dual x-ray absorptiometry (DEXA). Stress fractures were recorded on monthly calendars, and had to be confirmed by radiograph, bone scan, or magnetic resonance imaging. RESULTS: Seventeen participants had at least one stress fracture during follow-up. Higher intakes of calcium, skim milk, and dairy products were associated with lower rates of stress fracture. Each additional cup of skim milk consumed per day was associated with a 62% reduction in stress fracture incidence (P < .05); and a dietary pattern of high dairy and low fat intake was associated with a 68% reduction (P < .05). Higher intakes of skim milk, dairy foods, calcium, animal protein, and potassium were associated with significant (P < .05) gains in whole-body BMD and BMC. Higher intakes of calcium, vitamin D, skim milk, dairy foods, potassium, and a dietary pattern of high dairy and low fat were associated with significant gains in hip BMD. CONCLUSIONS: In young female runners, low-fat dairy products and the major nutrients in milk (calcium, vitamin D, and protein) were associated with greater bone gains and a lower stress fracture rate. Potassium intake was also associated with greater gains in hip and whole-body BMD.

The effect of obesity on quality of life in patients with diabetes and coronary artery disease.

BACKGROUND: Obesity increases the risk of type 2 diabetes and coronary artery disease (CAD). Because all 3 conditions may reduce quality of life, the extent to which obesity, diabetes, and CAD independently affect quality of life is uncertain. METHODS: Patients with type 2 diabetes and documented CAD participating in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial at 45 clinical sites in the United States and Canada were studied in a cross-sectional analysis of baseline data. Quality of life was assessed with the Duke Activity Status Index, the energy/fatigue and health distress scales from the Medical Outcome Study, and overall self-rated health status. RESULTS: Higher body mass index was significantly associated with worse scores on all 4 quality of life scales, even after adjustment for the severity of diabetes and CAD and other comorbid conditions. Use of insulin, angina, and current smoking were also associated with significantly lower quality of life on all 4 scales, independent of other factors. CONCLUSIONS: Obesity is associated with significantly reduced quality of life in patients with diabetes and CAD, independent of comorbid conditions.

Effect of race on the clinical outcomes in the bypass angioplasty revascularization investigation trial.

BACKGROUND: In observational studies, clinical outcomes for black patients with coronary disease have been worse than for white patients. There are few data from randomized trials comparing the outcomes of coronary revascularization between black patients and white patients. METHODS AND RESULTS: We analyzed data from the Bypass Angioplasty Revascularization Investigation randomized trial. At study entry, the 113 black patients had significantly higher rates of diabetes, hypertension, smoking, heart failure, and abnormal left ventricular function than the 1653 white patients. Black patients had significantly higher mortality than white patients (hazard ratio, 2.16; P<0.001), which remained significant after statistical adjustment for differences in baseline clinical characteristics (hazard ratio, 1.59; P=0.003). In a substudy of economic and quality of life outcomes, the 67 black patients had similar frequency of physician visits and use of evidence-based cardiac medications but significantly worse physical function scores than the 885 white patients. The effect of random assignment to either surgery or angioplasty on clinical outcomes was not significantly modified by race (interaction probability values >or=0.18). CONCLUSIONS: Clinical outcomes of black patients after coronary revascularization were worse than those of white patients in a clinical trial setting with similar treatment and access to care. The differences in outcome between black and white patients were not completely attributable to the greater levels of comorbidity among black patients at study entry.

Economic outcomes of treatment strategies for type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

BACKGROUND: The economic outcomes of clinical management strategies are important in assessing their value to patients. METHODS AND RESULTS: Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized patients with type 2 diabetes mellitus and angiographically documented, stable coronary disease to strategies of (1) prompt revascularization versus medical therapy with delayed revascularization as needed to relieve symptoms and (2) insulin sensitization versus insulin provision. Before randomization, the physician declared whether coronary artery bypass grafting or percutaneous coronary intervention would be used if the patient were assigned to revascularization. We followed 2005 patients for medical utilization and costs and assessed the cost-effectiveness of these management strategies. Medical costs were higher for revascularization than medical therapy, with a significant interaction with the intended method of revascularization (P<0.0001). In the coronary artery bypass grafting stratum, 4-year costs were $80 900 for revascularization versus $60 600 for medical therapy (P<0.0001). In the percutaneous coronary intervention stratum, costs were $73 400 for revascularization versus $67 800 for medical therapy (P<0.02). Costs also were higher for insulin sensitization ($71 300) versus insulin provision ($70 200). Other factors that significantly (P<0.05) and independently increased cost included insulin use and dose at baseline, female sex, white race, body mass index > or =30, and albuminuria. Cost-effectiveness based on 4-year data favored the strategy of medical therapy over prompt revascularization and the strategy of insulin provision over insulin sensitization. Lifetime projections of cost-effectiveness showed that medical therapy was cost-effective compared with revascularization in the percutaneous coronary intervention stratum ($600 per life-year added) with high confidence. Lifetime projections suggest that revascularization may be cost-effective in the coronary artery bypass grafting stratum ($47 000 per life-year added) but with lower confidence. CONCLUSIONS: Prompt coronary revascularization significantly increases costs among patients with type 2 diabetes mellitus and stable coronary disease. The strategy of medical therapy (with delayed revascularization as needed) appears to be cost-effective compared with the strategy of prompt coronary revascularization among patients identified a priori as suitable for percutaneous coronary intervention.

Economic evaluation of alternative strategies to treat patients with diabetes mellitus and coronary artery disease.

Diabetes mellitus and coronary artery disease (CAD) commonly coexist, and thus effective, cost-effective management strategies are needed. Intensive management of diabetes has been shown to increase medical costs while yielding better outcomes, with an acceptable cost-effectiveness ratio of <50,000 dollars per life-year added. On the basis of clinical trial findings in the 1970s and 1980s, coronary bypass surgery was cost-effective compared with medical therapy in the treatment of extensive CAD. Few trials have compared angioplasty with medical therapy, and its cost-effectiveness is not well established. The economic outcomes of contemporary coronary revascularization, especially angioplasty, compared with contemporary medical therapy must be evaluated. The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial will collect extensive economic data and examine the cost-effectiveness of alternative strategies to manage diabetes and CAD in patients with both disorders.

Medical costs and quality of life 10 to 12 years after randomization to angioplasty or bypass surgery for multivessel coronary artery disease.

BACKGROUND: Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. METHODS AND RESULTS: Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to 12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was 123,000 dollars versus 120,750 dollars for PTCA, yielding a cost-effectiveness ratio of 14,300 dollars/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. CONCLUSIONS: Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.

Quality of life and time trade-off utility measures in patients with coronary artery disease.

BACKGROUND: Contemporary clinical trials commonly measure quality of life and medical costs to establish whether therapies are both effective and cost effective. Cost-effectiveness analysis, however, requires a measure of patient utility or preferences for various health states. Because utilities are not often measured directly, we sought to develop a method of translating standard quality-of-life scales into a patient utility measure. METHODS: Five hundred fifty-three patients enrolled in the Bypass Angioplasty Revascularization Investigation Study of Economics and Quality of Life completed a battery of quality-of-life measures and a time trade-off utility assessment an average of 7.3 years after random assignment. RESULTS: The mean time trade-off score was 8.54 (SD = 2.53) out of a maximum of 10; median score was 9.95. The distribution of scores was skewed, with 12% of patients at the highest possible score of 10. Patients with recurrent angina had significantly lower time trade-off scores than patients without angina (mean 7.03 vs 8.70, P <.05). Time trade-off scores were moderately correlated with each quality-of-life measure (Spearman coefficients 0.38-0.52). Time trade-off scores could be predicted by combinations of 4 (r2 = 0.29), 5 (r2 = 0.31), or 6 (r2 = 0.32) variables. CONCLUSIONS: Time trade-off utility scores can be inferred from commonly used quality-of-life measures. Angina significantly reduces patient utility scores.