John F. Cursio

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008)

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

Depressive symptoms are related to progression of coronary calcium in midlife women: The Study of Women's Health Across the Nation (SWAN) Heart Study

BACKGROUND Major depression and depressive symptoms are associated with cardiovascular disease (CVD), but the impact of depression on early atherogenesis is less well known, particularly in women and minorities. This study examined whether depressive symptoms are associated with progression of coronary artery calcification (CAC) among women at midlife. METHODS The SWAN is a longitudinal, multisite study assessing health and psychologic factors in midlife women. An ancillary study (SWAN Heart) evaluated subclinical atherosclerosis in women who reported no history of CVD or diabetes. In 346 women, CAC was measured twice by electron beam computed tomography, an average of 2.3 years apart. Progression, defined as an increase by ≥10 Agatston units, was analyzed using relative risk (RR) regression. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression (CES-D) Scale. RESULTS Progression of CAC was observed in 67 women (19.1%). Each 1-SD-higher CES-D score at baseline related to a 25% increased risk of CAC progression (RR 1.25, 95% CI 1.06-1.47, P = .007), adjusting for age, time between scans, ethnicity, education, menopausal status, and known CVD risk factors. This risk was similar to the risk induced by body mass index (RR 1.31, 95% CI 1.11-1.54, P = .001) and systolic blood pressure (RR 1.28, 95% CI 1.06-1.55, P = .01). CONCLUSIONS Depressive symptoms were independently associated with progression of CAC in this cohort of midlife women. Depressive symptoms may represent a risk factor that is potentially modifiable for early prevention of CVD in women.

Sleep duration and weight change in midlife women: The SWAN sleep study

Short sleep duration has been associated with higher current BMI and subsequent weight gain. However, most prior longitudinal studies are limited by reliance on self‐reported sleep duration, and none accounted for the potential confounding effect of sleep‐disordered breathing. The associations of sleep duration with current BMI and BMI change were examined among 310 midlife women in the Study of Womens Health Across the Nation (SWAN) Sleep Study (2003‐2005).

Vitamin D is associated with atheroprotective high-density lipoprotein profile in postmenopausal women

BACKGROUND Low vitamin D has been associated with low levels of high-density lipoprotein (HDL) cholesterol, a marker of coronary risk. Whether atheroprotective HDL particle composition accounts for this association and whether fat affects this association is not known. OBJECTIVE To explore the association between HDL particle composition and 25-hydroxy vitamin D (25[OH]D) in post-menopausal women. METHODS Vitamin D levels and lipoprotein composition were assessed in fasting blood samples of apparently healthy women from a diverse Chicago community. Visceral (VAT) and subcutaneous (SAT) abdominal fat area were assessed using computed tomography. Total body fat mass was measured by dual-energy X-ray absorptiometry. RESULTS We enrolled 78 women (50% black; 50% white), age 48 to 64 years, all of whom were participants in a longitudinal study of fat patterning. They had a mean 25[OH]D of 31 ± 15 μg/L, HDL cholesterol 57±11 mg/dL, and large HDL particle subclass 8.6±3.4 μmol/L. In a multivariable-adjusted regression model, each 5 μg/L higher 25[OH]D predicted 0.57 μmol/L (95%CI 0.20-0.95) higher large HDL particles, independent of race, season, and total HDL particle concentration. This association was only partially confounded by total body fat mass (0.49, 95%CI 0.10-0.89), SAT (0.50, 95%CI 0.11-0.90), or VAT (0.37, 95%CI 0.01-0.74). Age did not significantly influence the strength of associations. CONCLUSIONS Higher 25[OH]D levels are associated with large HDL particles. This association is stronger than that of HDL cholesterol and only partially confounded by body fat. Theoretically, vitamin D may protect against cardiovascular risk by promoting formation of large HDL particles, affecting reverse cholesterol transport.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: A 20-year review from the southern network on adverse reactions (SONAR)

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Standardized admission and discharge templates to improve documentation of the joint commission on accreditation of healthcare organization performance markers

There is an increasing emphasis on the delivery of quality care and assessment for stroke patients. The Joint Commission (TJC) has offered a Disease-Specific Care Certification for stroke centers that are able to demonstrate exceptional stroke care by compliance with 10 performance markers. The 10 performance markers chosen were deep vein thrombosis (DVT) prophylaxis, discharged on antithrombotic therapy, patients with atrial fibrillation receiving anticoagulation therapy, tissue plasminogen activator (TPA) considered, antithrombotic medication within 48 hours, lipid profile, screen for dysphagia, stroke education, smoking cessation, and plan for rehabilitation considered (http://www.jointcommission. org/CertificationPrograms/PrimaryStrokeCenters/stroke_ pm_edition_2.htm). It has been recommended that comprehensive stroke centers have a stroke registry and also a data collection tool in place (Alberts et al., 2005). We created a Standardized Stroke Admission and Discharge Template to use at the University of Illinois at Chicago Medical Center to capture all 10 performance markers for each stroke patient. The goals of the templates were to prompt ordering of the performance markers, to improve documentation of the 10 performance markers, and to improve accuracy of the data abstraction. First, the standardized templates prompted the ordering physician to include each performance marker in the stroke orders. Secondly, quality stroke care may have been given before the use of the templates but may not have been captured because of poor documentation. The resident may have ruled out a certain treatment such as TPA but did not document clearly that this treatment was considered and the reason the treatment was not given. The new templates helped improve documentation by directly prompting the user to clearly document each performance marker. For example, if the treatment for TPAwas considered, the resident is prompted to document reperfusion therapy eligibility. Finally, the last goal of the templates was to improve the data abstraction. Before implementation of the templates, the individual abstracting data from the Care and Prevention Treatment Utilization Registry would search numerous areas in the medical record because performance markers were not being consistently documented in the same area each time. This may have caused the data abstractor not to have captured markers that may have been documented. The creation of the templates has facilitated a process to monitor quality improvement that was easy to follow and helped to abstract data. The purpose of this study was to evaluate whether instituting a standardized templatewould improve documentation of the 10 performance markers, to improve Volume 42 & Number 4 & August 2010 225

Platelet aggregation and recruitment with aspirin-clopidogrel therapy.

Background: Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown. Methods: Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B2 (11-dhTxB2)excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient. Results: Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB2 excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections. Conclusions: Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

Effect of Sex on Outcome after Recurrent Stroke in African Americans: Results from the African American Antiplatelet Stroke Prevention Study

BACKGROUND Sex-related disparities in stroke have been previously reported. However, the influence of sex on the outcome of recurrent stroke in African Americans is less clear. Our objective was to investigate the effect of sex on the outcome of recurrent nonfatal stroke in the African American Antiplatelet Stroke Prevention Study (AAASPS). METHODS The AAASPS is a double-blind, randomized, controlled trial of recurrent stroke prevention in African Americans. Participants (967 women and 842 men) with noncardioembolic ischemic stroke were assigned to receive ticlopidine or aspirin and were followed up for up to 2 years. The National Institutes of Health Stroke Scale (NIHSS) score, modified Barthel score (mBS), and Glasgow Outcome Scale (GOS) score were determined at enrollment, at prespecified times thereafter, and at the time of recurrent stroke. Survival analysis was used to test for a significant difference in the time to recurrent stroke between women and men. RESULTS Of the total 1809 subjects enrolled in AAASPS, 186 (89 women and 97 men) experienced recurrent nonfatal stroke. At enrollment, the NIHSS score (2.87 for women and 3.00 for men; P=.73), the mBS (18.26 for women and 18.52 for men; P=.47) and the GOS score (1.49 for women and 1.51 for men; P=.86) were not significantly different. In follow-up and at the time of stroke recurrence, the NIHSS score, mBS, and GOS score were similar for both groups, except for the mBS at the 6-month visit, which was lower in women (18.49) than in men (19.37) (P=.02). In the survival analysis, no significant difference in the time to recurrent stroke was found between women and men (P=.69). CONCLUSIONS Although sex-related stroke disparities have been reported, in the AAASPS cohort outcomes for recurrent nonfatal noncardioembolic ischemic stroke for women were not significantly different than for men. Differences in study populations and methodologies may explain discrepancies in results from the various studies.

Statistical and non linear mapping analysis of patient response to anti platelet therapy

Aspirin and clopidogrel combined irreversibly inhibits cyclooxygenase and reversibly inhibits ADP -dependent platelet aggregation. The combined effect on platelet recruitment is not described. Individual patient response to therapy is measurable. Thirty chronic ischemic stroke patients had platelet reactivity tests performed while taking aspirin alone followed by combination aspirin-clopidogrel over 3 months: ex-vivo platelet aggregation using a PAP 4 platelet aggregometer, recruitment by the method described by Valles et al., [2002] and urinary 11-dhTxB2 excretion by competitive enzyme linked immunosorbent assay. Compliance was monitored. Statistical methods included analysis of variance to compare variables of inhibition of platelet aggregation and recruitment between those on aspirin alone and combination therapy and longitudinal regression analysis with time as covariate to estimate inhibition of platelet recruitment. Non-linear mapping defined variable associations and interconnections in each patient. No bleeding or recurrent stroke occurred. One patient was non-compliant. Statistically significant difference was found (1) in favor of combination therapy for inhibition of ADP and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment for all methods tested, and (2) increasing inhibition of platelet recruitment over time. No statistical difference was found in urinary 11-dhTxB2 excretion between aspirin resistant and non resistant patients defined by platelet aggregation. Non-linear mapping showed patient-unique variable interconnections. Platelet inhibition with combination aspirin-clopidogrel increases over time in most patients. Urinary TxB2 excretion may not differentiate between aspirin resistant and non resistant patients defined by other measures of inhibition of platelet reactivity which uniquely connect in each patient.