Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-insights from the PLATelet inhibition and patient Outcomes (PLATO) trial.

BACKGROUND: Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits. METHODS: Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses. RESULTS: Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61). CONCLUSIONS: In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

Patterns of discharge antiplatelet therapy and late outcomes among 8,582 patients with bleeding during acute coronary syndrome: a pooled analysis from PURSUIT, PARAGON-A, PARAGON-B, and SYNERGY.

BACKGROUND: Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain. METHODS: We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT. RESULTS: Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03). CONCLUSIONS: Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes.

Assessing the economic attractiveness of coronary artery revascularization in chronic kidney disease patients.

Chronic kidney disease (CKD) is associated with increased morbidity and mortality in coronary artery disease (CAD) patients. We compared the economic attractiveness of CAD revascularization procedures in patients with and without CKD. Our population included 6218 patients with significant CAD undergoing cardiac catheterization at Duke University between 1996 and 2001, with follow-up through 2002. We investigated the influence of CKD (creatinine clearance < 60 mL/min) upon 3-year survival and medical costs in our CAD population. Coronary artery bypass graft (CABG) surgery was an economically attractive alternative vs. percutaneous coronary intervention (PCI) or medical therapy for all patients with left main disease, three-vessel CAD patients without CKD, and two-vessel CAD patients with CKD. Medical therapy was an economically attractive strategy vs. CABG surgery or PCI for three-vessel CAD patients with CKD, two-vessel CAD patients without CKD, and all single-vessel CAD patients.

Long-term mortality of patients undergoing cardiac catheterization for ST-elevation and non-ST-elevation myocardial infarction.

BACKGROUND: There are limited contemporary data comparing long-term outcomes after cardiac catheterization for ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). METHODS AND RESULTS: We studied patients undergoing cardiac catheterization for STEMI (n=2413) and NSTEMI (n=1974) between 1999 and 2005 with at least 1 significant coronary lesion > or =75%. We compared adjusted mortality rates over restricted time intervals and the differential impact of early revascularization on mortality stratified by ST-elevation status. Between 1999 and 2007, 1274 patients died, with a median follow-up of 4 years. A piece-wise analysis showed a higher adjusted mortality risk for STEMI during the first 2 months (adjusted hazard ratio, 1.85; 95% confidence interval, 1.45 to 2.38) and a lower adjusted mortality risk for STEMI after 2 months (adjusted hazard ratio, 0.68; 95% confidence interval, 0.59 to 0.83). Compared with late or no revascularization, early revascularization was associated with a lower adjusted risk of mortality for both STEMI (adjusted hazard ratio, 0.73; 95% confidence interval, 0.58 to 0.90) and NSTEMI (adjusted hazard ratio, 0.76; 95% confidence interval, 0.65 to 0.89) (P for interaction=0.22). CONCLUSIONS: Among a contemporary cohort of acute MI patients with significant coronary disease during cardiac catheterization, STEMI was associated with a higher risk of short-term mortality, but NSTEMI was associated with a higher risk of long-term mortality. Early revascularization was associated with a similar improvement in long-term outcomes for both STEMI and NSTEMI. These data suggest that in clinical investigations of early revascularization among patients with NSTEMI, extended follow-up may be necessary to demonstrate treatment benefit.

Do income level and race influence survival in patients receiving hemodialysis?

BACKGROUND: Residence in a lower-income area has been associated with higher mortality among patients receiving dialysis. We sought to determine whether these differences persist and whether the effect of income-area on mortality is different for African Americans versus patients of other races. METHODS: We evaluated relationships between lower- and higher-income versus middle-income area residence and mortality to 5 years after adjusting for differences in baseline clinical, dialysis facility, and socioeconomic characteristics in 186,424 adult patients with end-stage renal disease initiating hemodialysis at stand-alone facilities between 1996 and 1999. We also compared mortality differences between race and income level groups using non-African Americans residing in middle-income areas as the reference group. RESULTS: Patients with end-stage renal disease who reside in lower-income areas were younger and more frequently African American. After adjustment, there were no mortality differences among income level groups. However, African Americans in all income level groups had lower adjusted mortality compared with the reference group (lower-income hazard ratio [HR]=0.771, 95% confidence interval [CI], 0.736-0.808; middle-income HR=0.755, 95% CI, 0.730-0.781; higher-income HR=0.809, 95% CI, 0.764-0.857), whereas adjusted mortality was similar among non-African-American income level groups (lower-income HR=1.019, 95% CI, 0.976-1.064; higher-income HR=1.003, 95% CI, 0.968-1.039). CONCLUSION: Adjusted survival for patients receiving hemodialysis in all income areas was similar. However, this result masks the paradoxically higher survival for African American versus patients of other race and demonstrates the need to adjust for differences in demographic, clinical, provider, and socioeconomic status characteristics.

Quality of life with defibrillator therapy or amiodarone in heart failure.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy significantly prolongs life in patients at increased risk for sudden death from depressed left ventricular function. However, whether this increased longevity is accompanied by deterioration in the quality of life is unclear. METHODS: In a randomized trial, we compared ICD therapy or amiodarone with state-of-the-art medical therapy alone in 2521 patients who had stable heart failure with depressed left ventricular function. We prospectively measured quality of life at baseline and at months 3, 12, and 30; data collection was 93 to 98% complete. The Duke Activity Status Index (which measures cardiac physical functioning) and the Medical Outcomes Study 36-Item Short-Form Mental Health Inventory 5 (which measures psychological well-being) were prespecified primary outcomes. Multiple additional quality-of-life outcomes were also examined. RESULTS: Psychological well-being in the ICD group, as compared with medical therapy alone, was significantly improved at 3 months (P=0.01) and at 12 months (P=0.003) but not at 30 months. No clinically or statistically significant differences in physical functioning among the study groups were observed. Additional quality-of-life measures were improved in the ICD group at 3 months, 12 months, or both, but there was no significant difference at 30 months. ICD shocks in the month preceding a scheduled assessment were associated with a decreased quality of life in multiple domains. The use of amiodarone had no significant effects on the primary quality-of-life outcomes. CONCLUSIONS: In a large primary-prevention population with moderately symptomatic heart failure, single-lead ICD therapy was not associated with any detectable adverse quality-of-life effects during 30 months of follow-up.

Empirical estimation of life expectancy from large clinical trials: use of left-truncated, right-censored survival analysis methodology.

In the current era of ever-increasing health care costs, economic analyses are an essential component in the comprehensive evaluation of new medical interventions. Cost-effectiveness analysis (CEA)--the most common form of economic analysis used in medicine--aids policy-makers in determining how to allocate finite health care dollars among possible alternative therapies. CEA relates the incremental benefits of a new technology to its incremental costs in a cost-effectiveness (CE) ratio. Although the generally agreed-upon standard of presentation for the CE ratio is the lifetime perspective (incremental lifetime cost to add one life year), this perspective presents an obvious challenge to the statistical analyst. Most large clinical trials collect limited follow-up data, and yet their findings form the basis of therapeutic recommendations that often extend far beyond the limits of the empirical data. Although clinical practice guidelines do not yet require explicit modeling to examine the long-term implications of their recommendations, health policy analyses routinely rely upon such extrapolations. This paper describes methods for using empirical patient-level data to extrapolate survival in large clinical trials and cohorts beyond a limited follow-up period in which most patients remain alive in order to estimate the entire survival distribution for a cohort of patients. We accomplish this task through a novel combination of models that estimate the hazard rate not only as a function of time but also as a function of patient age. Extrapolation of survival beyond a limited time frame is made possible by capitalizing on the extensive latitude of survival information available across the range of ages represented in the data. Variations in approach are presented, and issues arising in these analyses are discussed. The proposed methodology is developed, applied, and evaluated in both a large clinical trial cohort with 5-year follow-up on over 23,000 patients and a large observational database with long-term follow-up on over 4000 patients.

Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin.

Follistatin binds and neutralizes members of the TGFbeta superfamily including activin, myostatin, and growth and differentiation factor 11 (GDF11). Crystal structure analysis of the follistatin-activin complex revealed extensive contacts between follistatin domain (FSD)-2 and activin that was critical for the high-affinity interaction. However, it remained unknown whether follistatin residues involved with myostatin and GDF11 binding were distinct from those involved with activin binding. If so, this would allow development of myostatin antagonists that would not inhibit activin actions, a desirable feature for development of myostatin antagonists for treatment of muscle-wasting disorders. We tested this hypothesis with our panel of point and domain swapping follistatin mutants using competitive binding analyses and in vitro bioassays. Our results demonstrate that activin binding and neutralization are mediated primarily by FSD2, whereas myostatin binding is more dependent on FSD1, such that deletion of FSD2 or adding an extra FSD1 in place of FSD2 creates myostatin antagonists with vastly reduced activin antagonism. However, these mutants also bind GDF11, indicating that further analysis is required for creation of myostatin antagonists that will not affect GDF11 activity that could potentially elicit GDF11-induced side effects in vivo.

Re-evaluating the volume-outcome relationship in hemodialysis patients.

OBJECTIVES: We sought to determine whether dialysis patient mortality rates are associated with differences in dialysis facility size, and whether this relationship differs among higher risk diabetic and lower-risk non-diabetic patients. METHODS: Using 186,554 adult end-stage renal disease patients initiating hemodialysis at standalone facilities in the United States between 1996 and 1999, we evaluated relationships between dialysis facility size and survival to 5 years. We performed separate analyses for patients with and without diabetes as their primary cause of end-stage renal disease. Facility size was defined according to the number of hemodialysis patients at year's end (smallor=120). RESULTS: Increasing facility size was associated with a reduced risk of mortality at 4 years for both diabetic (HR=0.983 per 10 unit increase, 95% CI=0.967, 0.999) and non-diabetic patients (HR 0.977 per 10 unit increase, 95% CI=0.963, 0.992) dialyzing in small facilities, and for diabetic patients (HR 0.989 per 10 unit increase, 95% CI=0.980, 0.998) dialyzing in medium size facilities. CONCLUSIONS: Smaller facility size is associated with increasing long-term mortality for in-center hemodialysis patients. This relationship appears to be more pronounced among higher-risk diabetic vs. lower-risk non-diabetic patients.

Mortality by dialysis modality among patients who have end-stage renal disease and are awaiting renal transplantation.

Comparing outcomes related to dialysis modality is complicated by selection bias introduced by patients and physicians. To address the impact of selection bias, this study compared mortality by initial dialysis modality among patients who had ESRD and were placed on the transplant waiting list. This study was a historical prospective cohort of 12,568 patients in the United States who initiated dialysis between May 1, 1995, and October 31, 1998, and were placed on the transplant waiting list before dialysis initiation. Two-year mortality was compared using Kaplan-Meier curves and Cox proportional hazards models that analyzed patients primarily using an intention-to-treat approach and separately censored patients on a modality switch. At 2 yr, the unadjusted mortality rate was 6.6% among peritoneal dialysis (PD) patients compared with 6.9% among hemodialysis (HD) patients (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.82 to 1.23). After controlling for differences in baseline characteristics, comorbidities, and laboratory variables, the selection of PD versus HD remained associated with a similar 2-yr mortality risk (HR 1.03; 95% CI 0.83 to 1.28). In separate models, 2-yr mortality associated with PD versus HD was significant among patients with body mass index (BMI) > or = 26 kg/m2 (HR 1.37; 95% CI 1.01 to 1.83) but not among patients with BMI < 26 kg/m2 (HR 0.81; 95% CI 0.61 to 1.07). Results were similar after censoring on a modality switch. In conclusion, although choice of initial dialysis modality seems to be associated with equivalent outcomes among patients who have ESRD and are placed on the transplant waiting list, patients with BMI > or = 26 kg/m2 have increased 2-yr mortality associated with the selection of PD versus HD. Because the interpretation of observational data is highly affected by residual confounding and selection bias, further efforts should focus on the formation and testing of hypotheses to improve dialysis delivery.