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Stroke With Transfusions Changing to Hydroxyurea (SWiTCH Clinical Trials.gov NCT00122980), an NHLBI-sponsored Phase III multicenter ...trial, compared chronic blood transfusions/chelation to hydroxyurea/phlebotomy for the reduction of recurrent stroke and improvement in iron overload management in children with sickle cell anemia (SCA) and history of overt stroke. To date, however, phlebotomy to manage iron overload has not been commonly performed in children, especially those with SCA.
To describe the experience with SWiTCH phlebotomy procedures, including success rate, associated adverse events, and effect on liver iron stores.
Quantitative liver iron concentration (LIC) was measured by liver biopsy at study entry. Only subjects with LIC > 5 mg Fe/gram dry weight liver (DWL) were eligible for randomization. Those randomized to hydroxyurea/phlebotomy received decreasing volumes of monthly transfusion during hydroxyurea dose escalation, which lasted 4–9 months. Phlebotomy was performed every 4±1 weeks after discontinuation of transfusions. The prescribed phlebotomy volume was 10 mL/kg (maximum 500 mL) for Hb ≥ 8.0 gm/dL, and 5 mL/kg for Hb 7.0–7.9 gm/dL. Phlebotomy was held if Hb was <7.0 gm/dL. Phlebotomy was performed over 30 minutes with immediate normal saline replacement, typically using peripheral venous access. Exit LIC by liver biopsy was obtained in those completing 30 months of therapy. Ferritin was monitored monthly in all subjects using a centralized laboratory.
Sixty-seven children (mean age 13.0 ± 4.0 years; range 5.2–19.0 years) with history of previous stroke and transfusion therapy for an average of 7.4 ± 3.8 years (range 1.5–15.5 years) were randomized to the hydroxyurea/phlebotomy arm. Most of them had also received chelation therapy: 47 (71%) with deferoxamine for an average of 4.8 ± 3.2 years, and 57 (86%) with deferasirox for 1.5 ± 0.8 years prior to study entry. Their average entry LIC was 16.5 ± 9.4 mg/gram DWL. Sixty of 67 children (90%) successfully transitioned to hydroxyurea after 7.2 ± 2.4 months of transfusion overlap; one subject had a stroke during overlap and six failed to demonstrate adequate response/compliance to hydroxyurea to safely discontinue transfusions. These 60 subjects received an average of 8 ± 3 transfusions providing 63 ± 44 mL/kg PRBCs before completing transition and commencing phlebotomy, and 3 ± 3 transfusions providing 19 ± 20 mL/kg PRBCs after starting phlebotomy, for various clinical indications. During the course of the study, a total of 935 phlebotomies were performed (mean 16 per subject) removing an average total volume of 127 ± 74 mL/kg per subject. The mean pre-phlebotomy Hb level on hydroxyurea (9.1 gm/dL) was not significantly different than the mean pre-transfusion Hb during the transfusion overlap period (9.0 gm/dL). Mean ferritin for these 60 subjects on the hydroxyurea/phlebotomy arm decreased from 3523 ± 2150 ng/mL at study entry to 2227 ± 1646 ng/mL (p<0.0001) at exit; and decreased in 50 of 60 subjects. For the 23 patients on the hydroxyurea/phlebotomy arm who completed 30 months of study treatment, the average LIC was unchanged (18.5 mg Fe/gram DWL at entry compared to 18.1 mg Fe/gram at exit, p=0.817). However, average ferritin level for these subjects was significantly lower at exit (4216 ± 2799 ng/mL vs 2356 ± 2032 ng/mL, respectively, p=0.0003). Of 968 protocol-directed phlebotomy procedures, 935 (97%) were performed; 94% of which were at full prescribed volume. Of the 33 phlebotomy procedures that were not performed, 11 were held due to Hb < 7.0 gm/dL and 9 due to poor venous access. There were only 33 grade 2 adverse events (3.5% prevalence) reported in 12 subjects and no serious adverse events. The most common complication was hypotension (9 events; 5 subjects) followed by dizziness, syncope, headache and weakness. Six subjects had a recurrent stroke but there was no temporal relationship to the phlebotomy procedures.
Therapeutic phlebotomies were well-tolerated and did not result in worsening anemia or stroke recurrence in this cohort of children with SCA and previous stroke switched to hydroxyurea. Although ferritin levels decreased significantly, we did not demonstrate an overall decrease in LIC in this heavily iron overloaded cohort, most likely due to continued iron loading with transfusions in the overlap period and subsequent short duration of phlebotomy.
Off Label Use: Use of hydroxyurea in children with sickle cell anemia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Effective allocation of medical resources in stable chest pain patients requires the accurate diagnosis of coronary artery disease and the stratification of future cardiac risk. We studied the ...relative predictive value for cardiac death of 3 commonly applied noninvasive strategies, clinical assessment, stress electrocardiography, and myocardial perfusion tomography, in a large, multicenter population of stable angina patients. The multicenter observational series comprised 7 community and academic medical centers and 8,411 stable chest pain patients. All patients underwent pretest clinical screening followed by stress (exercise 84% or pharmacologic 16%) electrocardiography and myocardial perfusion tomography. Risk-adjusted multivariable Cox proportional hazards models were developed to predict cardiac death. Kaplan-Meier rates of time to cardiac catheterization were also computed. Cardiac mortality was 3% during the 2.5 ± 1.5 years of follow-up. The number of infarcted vascular territories and pretest clinical risk factors were strong predictors of cardiac mortality, whereas the number of ischemic vascular territories gained increasing importance when determining post-test resource use requirements (i.e., the decision to perform cardiac catheterization). Exertional ST-segment depression in a population with a high frequency of electrocardiographic abnormalities at rest was not a significant differentiator of cardiac death risk. Stable chest pain patients are accurately identified as being at high risk for near-term cardiac events by both physicians’ screening clinical evaluation and by the results of stress myocardial perfusion imaging. Disease management strategies for stable chest pain patients aimed at risk reduction should incorporate knowledge of relevant end points in treatment and guideline development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We assessed the relation of abnormal predischarge noninvasive test results to outcomes in postmyocardial infarction patients. We included series published from 1980 to 1995 containing only myocardial ...infarction patients, enrolling most patients after 1980, testing within 6 weeks of infarction, having follow-up rates > 80%, and having 2 × 2 frequency outcome rates for test results, that were the latest of multiple reports. Sensitivity, specificity, and predictive values were calculated for test results for 1-year outcomes (cardiac death, cardiac death or reinfarction). Univariable and summary odds were calculated for test results. Reports (n = 54) included a total of 19,874 patients and were primarily retrospective (76%) and small series (35% of reports included < 5 deaths). One-year mortality ranged from 2.5% for pharmacologic stress echocardiography to 9.3% for exercise radionuclide angiography. Positive predictive values for most noninvasive risk markers were < 0.10 for cardiac death and 0.20 for death or reinfarction. Electrocardiographic, symptomatic, and scintigraphic risk markers of ischemia (ST-segment depression, angina, a reversible defect) were less sensitive (≤44%) for identifying morbid and fatal outcomes than markers of left ventricular dysfunction or heart failure (exercise duration, impaired systolic blood pressure response, and peak left ventricular ejection fraction). The positive predictive value of predischarge noninvasive testing is low. Markers of left ventricular dysfunction appear to be better predictors than markers of ischemia. Limitations of the literature—small samples and widely varying event rates—impede our ability to discern the accuracy of predischarge noninvasive testing. More rigorous, controlled trials are required to elucidate the relative value of these tests for risk stratification.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Following approval of the fat replacer olestra for use in preparing savory snacks, Procter & Gamble implemented a postmarketing surveillance program to monitor marketplace introduction. Three and ...one-half percent of all health effects reported by consumers to the surveillance toll-free number were allergy-type symptoms (e.g., rash, itching, edema, hives, dyspnea). Because of these reports, we investigated whether olestra or some component of olestra snacks was a likely allergen in some subset of the population. A single center, randomized, double-blind, placebo-controlled, within-subject crossover food challenge study was conducted to confirm or refute the allergenicity of olestra snacks. Of the 65 subjects who reported symptoms consistent with immediate hypersensitivity to olestra's postmarketing surveillance program, 14 men and women traveled to the Arkansas Children's Hospital Research Institute to participate in this study. Each subject underwent a standard skin prick test at the beginning of the study, to help determine what component, if any, of the olestra product was allergenic. Following the skin prick test, subjects ate in random order, olestra-containing potato chips and regular fat-containing potato chips. The dose of potato chips consumed at each challenge was at least the amount alleged to have caused the symptoms that prompted the consumer to phone the postmarketing surveillance toll-free number. No subject experienced an allergic reaction after consuming the olestra-containing chips. Nor did any subject elicit a positive response to olestra following the skin prick testing. Two subjects had positive reactions consistent with immediate hypersensitivity after consuming the regular-fat, placebo potato chips. The results of this study confirm that olestra is unlikely to have an allergenic potential.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
This study was performed to determine whether gated equilibrium radionuclide angiogram measurements of left ventricular function during rest and exercise add independent information to clinical and ...catheterization data in predicting cardiac death. METHODS AND RESULTS: The study population consisted of 863 consecutive patients undergoing exercise gated equilibrium radionuclide angiography within 90 days of cardiac catheterization with data prospectively entered into the Duke Cardiovascular Database. All patients were symptomatic, medically treated, with significant coronary artery disease and had undergone follow-up for < or = 6 yr. A univariable and multivariable Cox regression analysis was utilized to evaluate the independent power in predicting 147 (17.0%) cardiac deaths. This risk-adjusted analysis revealed that only rest and exercise ejection fraction as well as maximum workload contained independent prognostic information; the nuclear variables contributed 63% of the total information within the model. A multivariable model including exercise ejection fraction and clinical history variables provided slightly more prognostic information than the combination of cardiac catheterization and clinical data. CONCLUSION: Multigated equilibrium radionuclide angiography is a key predictor of cardiac death when compared to clinical and cardiac catheterization data in patients with symptomatic, medically treated coronary artery disease. Thus, long-term outcome for patients may be determined by utilizing this noninvasive tool even when clinical and cardiac catheterization data are also available.
This investigation assesses the prognostic value of radionuclide measurements of cardiac function in patients undergoing coronary artery bypass grafting (CABG). Radionuclide angiograms during ...exercise and at rest were obtained in 182 patients before (≤30 days), early (≤3 months), and late (≤3 years) after CABG. Cox proportional hazard regression analysis was used to identify independent predictors of 44 cardiac deaths that occurred a median 12 years after bypass. Although the exercise ejection fractions before and early after CABG were significantly related to subsequent cardiac death (chi-square = 10.84, p = 0.001, and chi-square = 7.4, p = 0.006, respectively), the late postoperative exercise ejection fraction was the strongest predictor (chi-square = 13.9, p = 0.0002), contributing above and beyond clinical and catheterization data. These data document the validity of the exercise ejection fraction as an important predictor of cardiac death after CABG and suggest the potential clinical application of serial measurements of the exercise ejection fraction as an important noninvasive adjunct to postoperative evaluation of these patients.
Exercise ejection fractions before, early, and late after bypass were significantly related to cardiac death (chi-square = 10.84, p = 0.001; chi-square = 7.4, p = 0.006; and chi-square = 13.9, p = 0.0002, respectively). Moreover, peak exercise ejection fraction from the last radionuclide assessment contributed significant information beyond the clinical history or catheterization data (p = 0.0002).
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
