ABSTRACT: The Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC) study demonstrated a shortened time to extubation in children younger than 5 months old undergoing cardiopulmonary bypass for congenital heart surgery with triiodothyronine supplementation. Cardiopulmonary bypass precipitates a systemic inflammatory response that affects recovery, and triiodothyronine is related to cytokine mediators of inflammation. We sought to investigate the preoperative cytokine levels by age and relationship to the triiodothyronine levels and to examine the effect of the cytokine levels on the time to extubation.
We measured 6 cytokines at preoperative time 0 and 6 and 24 hours after crossclamp removal in 76 subjects.
The preoperative cytokine levels were related to both the triiodothyronine levels and the patient age. The postoperative cytokine levels were predictive of the triiodothyronine levels at 6, 12, 24, and 72 hours. Preoperative CCL4 was associated with an increased chance of early extubation. Inclusion of the cytokines did not change the relationship of triiodothyronine to the time to extubation, and the postoperative course of interleukin-6 was independently associated with a decreased chance of early extubation.
The preoperative and postoperative cytokine levels, in particular, interleukin-1β, showed complex time-dependent relationships with triiodothyronine. The data suggest that cytokine-mediated suppression of triiodothyronine plays an important role in determining the clinical outcome after cardiopulmonary bypass.
The Journal of thoracic and cardiovascular surgery 06/2012; 144(4):938-943.e2. · 3.41 Impact Factor
ABSTRACT: The impact of individual antiarrhythmic drugs (AADs) on mortality and hospital stay in atrial fibrillation (AF) was evaluated.
Cardiovascular (CV) outcomes in AF patients receiving pharmacologic rhythm control therapy have not been compared with rate control therapy on the basis of AAD selection.
We compared CV outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial in subgroups defined by the initial AAD selected with propensity score matched subgroups from the rate arm (Rate).
Seven hundred twenty-nine amiodarone patients, 606 sotalol patients, and 268 Class 1C patients were matched. The composite outcome of mortality or cardiovascular hospital stays (CVH) showed better outcomes with Rate compared with amiodarone (hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.03 to 1.36, p = 0.02), sotalol (HR: 1.32, 95% CI: 1.13 to 1.54, p < 0.001), and Class 1C (HR: 1.22, 95% CI: 0.97 to 1.56, p = 0.10). There was a nonsignificant increase in mortality with amiodarone (HR: 1.20, 95% CI: 0.94 to 1.53, p = 0.15) with the risk of non-CV death being significantly higher with amiodarone versus Rate (HR: 1.11, 95% CI: 1.01 to 1.24, p = 0.04). First CVH event rates at 3 years were 47% for amiodarone, 50% for sotalol, and 44% for Class 1C versus 40%, 40%, and 36%, respectively, for Rate (amiodarone HR: 1.20, 95% CI: 1.03 to 1.40, p = 0.02, sotalol HR: 1.364, 95% CI: 1.16 to 1.611, p < 0.001, Class 1C HR: 1.24, 95% CI: 0.96 to 1.60, p = 0.09). Time to CVH with intensive care unit stay or death was shorter with amiodarone (HR: 1.22, 95% CI: 1.02 to 1.46, p = 0.03).
In AFFIRM, composite mortality and CVH outcomes differed for Rate and AADs due to differences in CVH; CVH event rates during follow-up were high for all cohorts, but they were higher for all groups on AADs. Death, intensive care unit hospital stay, and non-CV death were more frequent with amiodarone.
Journal of the American College of Cardiology 11/2011; 58(19):1975-85. · 14.16 Impact Factor
ABSTRACT: Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome.
The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment (P=0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. (P=0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7-22) for placebo and 20 hours (CI, 16-45) for Triostat and (hazard ratio, 0.60; P=0.0220).
T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417.
Circulation 09/2010; 122(11 Suppl):S224-33. · 14.74 Impact Factor
ABSTRACT: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.
This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days.
The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02).
These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.
Drug and alcohol dependence 06/2009; 104(1-2):133-9. · 3.60 Impact Factor
ABSTRACT: In the Atrial Fibrillation Follow-up Investigation of Rhythm Management study, preexisting pulmonary disease did not preclude the use of amiodarone. Preexisting pulmonary disease was associated with a higher risk of pulmonary death and had a higher risk of diagnosed amiodarone pulmonary toxicity. However, use of amiodarone in the presence of preexisting pulmonary disease did not increase pulmonary death and all-cause mortality rates. Cautious use of amiodarone to treat atrial fibrillation appears acceptable in elderly patients with atrial fibrillation, even if preexisting pulmonary disease is present.
The American Journal of Cardiology 03/2005; 95(3):404-5. · 3.37 Impact Factor
ABSTRACT: The objective of the current study was to determine the clinical factors that were associated with abandonment of a rate-control or a rhythm-control strategy in patients with atrial fibrillation (AF).
Although the AFFIRM Study demonstrated that outcomes are similar with a primary strategy of rate-control or rhythm-control for AF, there may be clinical or demographic factors associated with abandonment of the initial treatment strategy. Knowledge of these risk factors would be useful so that patients may be given appropriate initial therapy and, as appropriate, switched to alternative treatments earlier.
Patients in the AFFIRM Study were subdivided into those who were maintained on their initial treatment strategy versus those who abandoned initial treatment strategy for alternative therapies. We determined the clinical and demographic factors associated with change in initial treatment strategy.
At 5 years the original treatment strategy was maintained in 85% of the patients in the rate-control arm versus 62% of those in the rhythm-control arm (P <.0001). Length of the qualifying episode of AF was associated with abandonment of both rhythm-control and rate-control strategies. Antiarrhythmic drug failure before randomization and a history of thyroid disease also were associated with abandonment of rhythm-control. Patients were more likely to maintain rate-control if they already had an implanted pacemaker or if they were older than 75 years, while an ejection fraction <30% was associated with abandonment of the rate-control strategy.
In patients with AF, rhythm-control strategies are abandoned significantly more often than rate-control strategies. Patients with long durations of AF on presentation or previous antiarrhythmic drug failure might be considered for rate-control as initial treatment.
American heart journal 02/2005; 149(2):304-8. · 4.65 Impact Factor
ABSTRACT: Atrial fibrillation is the most common type of sustained cardiac arrhythmia, but recent trials have identified no clear advantage of rhythm control over rate control. Consequently, economic factors often play a role in guiding treatment selection.
To estimate the cost-effectiveness of rhythm-control versus rate-control strategies for atrial fibrillation in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM).
Retrospective economic evaluation. Nonparametric bootstrapping was used to estimate the distribution of incremental costs and effects on the cost-effectiveness plane.
Data on survival and use of health care resources were obtained for all 4060 AFFIRM participants. Unit costs were estimated from various U.S. databases.
Patients with atrial fibrillation who were 65 years of age or who had other risk factors for stroke or death, similar to those enrolled in AFFIRM.
Mean follow-up of 3.5 years.
Management of patients with atrial fibrillation with antiarrhythmic drugs (rhythm control) compared with drugs that control heart rate (rate control).
Mean survival, resource use, costs, and cost-effectiveness.
A mean survival gain of 0.08 year (P = 0.10) was observed for rate control. Patients in the rate-control group used fewer resources (hospital days, pacemaker procedures, cardioversions, and short-stay and emergency department visits). Rate control costs 5077 dollars less per person than rhythm control.
Cost savings ranged from 2189 dollars o 5481 dollars per person. Rhythm control was more costly and less effective than rate control in 95% of the bootstrap replicates over a wide range of cost assumptions.
Resource use was limited to key items collected in AFFIRM, and the results are generalizable only to similar patient populations with atrial fibrillation.
Rate control is a cost-effective approach to the management of atrial fibrillation compared with maintenance of sinus rhythm in patients with atrial fibrillation similar to those enrolled in AFFIRM.
Annals of internal medicine 12/2004; 141(9):653-61. · 16.73 Impact Factor
ABSTRACT: The purpose of this study was to examine possible alternatives for death, particularly hospitalization for cardiovascular reasons (CV hospitalization), as an endpoint in studies of atrial fibrillation (AF) using the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) database.
AF is associated with increased mortality, but large numbers of patients are needed to demonstrate even a moderate effect of a therapy on mortality.
AFFIRM studied 4,060 patients with AF, randomized to either rate-control or rhythm-control strategy with death as the primary endpoint.
Only CV hospitalization occurred more frequently than death. Like death, CV hospitalization was more frequent in the rhythm-control arm (46% vs 36%, P < .001) overall but not in a cohort that attempted to exclude those CV hospitalizations possibly related to treatment strategy (e.g., cardioversion, 24% vs 27%). In either model there was no interaction of CV hospitalization (analyzed as a time-dependent covariate) with treatment arm (P = .18 and P = .21, respectively). CV hospitalization was highly predictive of death in both treatment arms (P < .001) in either model, but after this event, there was no difference in time to death. A composite endpoint of CV hospitalization combined with death might increase power and reduce the size of trials of therapy for AF in such patients.
In patients with AF such as those in the AFFIRM study, CV hospitalization has many attributes of a surrogate for mortality. More research on CV hospitalization, alone or as part of a composite endpoint, is warranted.
Heart Rhythm 11/2004; 1(5):531-7. · 4.10 Impact Factor
ABSTRACT: To assess the long-term cure rate for treatment of lentigo maligna (LM) and lentigo maligna melanoma (LMM) by means of a staged, margin-controlled, vertical-edged excision with rush permanent specimens and a radial sectioning technique.
Retrospective follow-up study.
University-affiliated and private-practice dermatologic surgery clinics.
Fifty-nine patients treated for 55 LMs and 7 LMMs between January 1, 1990, and December 31, 2001.
The technique included vertical excision with initial 2- to 3-mm margins examined by rush permanent sections (prepared and read within 24 hours). Further excision took place as guided by histologic findings. Data on patient and lesion characteristics were obtained via a medical chart review. Patients were then contacted and examined for local recurrence. Biopsies were performed on all patients with possible recurrence on clinical examination.
Local recurrence of LM or LMM.
After a mean follow-up of 57 months (median, 54 months; 293.8 person-years), 95% of patients were free of recurrence. Three patients had local recurrence and no patients had evidence of metastasis. Two of the 3 local recurrences were of previously excised LM, and 1 was of an LMM. Half (32) of all lesions required 2 or more stages. One required more than 4 stages. The average margin of excision was 0.55 cm. Three of the 58 lesions read as LM on biopsy were found to have invasive disease (LMM) at the time of definitive excision.
The technique described herein for the treatment of LM and LMM provides a long-term disease-free survival of 95%. The cure rate is greater than that reported for standard excision and is similar to that for other margin-control techniques. To our knowledge, this is the largest reported study and has the longest follow-up for this excision method for LM and LMM.
Archives of Dermatology 06/2004; 140(5):552-8. · 3.89 Impact Factor
ABSTRACT: Losses to follow-up and administrative censoring can cloud the interpretation of trial-based economic evaluations. A number of investigators have examined the impact of different levels of adjustment for censoring, including nonadjustment, adjustment of effects only, and adjustment for both costs and effects. Nevertheless, there is a lack of research on the impact of censoring on decision-making. The objective of this study was to estimate the impact of adjustment for censoring on the interpretation of cost-effectiveness results and expected value of perfect information (EVPI), using a trial-based analysis that compared rate- and rhythm-control treatments for persons with atrial fibrillation.
Three different levels of adjustment for censoring were examined: no censoring of cost and effects, censoring of effects only, and censoring of both costs and effects. In each case, bootstrapping was used to estimate the uncertainty incosts and effects, and the EVPI was calculated to determine the potential worth of further research.
Censoring did not impact the adoption decision. Nevertheless, this was not the case for the decision uncertainty or the EVPI. For a threshold of $50,000 per life-year, the EVPI varied between $626,000 (partial censoring) to $117 million (full censoring) for the eligible US population.
The level of adjustment for censoring in trial-based cost-effectiveness analyses can impact on the decisions to fund a new technology and to devote resources for further research. Only when censoring is taken into account for both costs and effects are these decisions appropriately addressed.
Value in Health 11(3):365-75. · 2.19 Impact Factor