Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke).

BACKGROUND AND PURPOSE: We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. METHODS: Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 µg/kg bolus) followed by infusion of either 1 (low dose) or 3 µg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). RESULTS: Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. CONCLUSIONS: In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.

Thrombelastography detects the anticoagulant effect of rivaroxaban in patients with stroke.

BACKGROUND AND PURPOSE: Factor Xa inhibitors are prescribed for stroke prevention in atrial fibrillation. Managing such patients is challenging especially if they are eligible for thrombolysis because there is no rapidly available test to detect the effect of such medications. Thrombelastography analyzes the dynamics of coagulation and can be rapidly performed. We sought to determine whether thrombelastography can detect the anticoagulation effect of factor Xa inhibitors in patients with stroke. METHODS: Blood from 10 patients with stroke was analyzed by thrombelastography at baseline and 2 to 18 hours after rivaroxaban administration. RESULTS: Increased R, K, and δ were seen at 2, 4, and 6 hours, while G, maximum amplitude, α-angle, and LY30 were decreased. Baseline R was 5.8±0.5 when compared with 11.4±1.0 at 2 hours. R remained prolonged at 18 hours. Other thrombelastography parameters were normal by 18 hours. CONCLUSIONS: Thrombelastography can detect the anticoagulant effect of factor Xa inhibitors in patients with stroke and might be useful in the emergency management of those eligible for thrombolysis.

Coordination and management of multisite complementary and alternative medicine (CAM) therapies: experience from a multisite reflexology intervention trial.

BACKGROUND: Multisite randomized clinical trials allow for increased research collaboration among investigators and expedite data collection efforts. As a result, government funding agencies typically look favorably upon this approach. As the field of complementary and alternative medicine (CAM) continues to evolve, so do increased calls for the use of more rigorous study design and trial methodologies, which can present challenges for investigators. PURPOSE: To describe the processes involved in the coordination and management of a multisite randomized clinical trial of a CAM intervention. METHODS: Key aspects related to the coordination and management of a multisite CAM randomized clinical trial are presented, including organizational and site selection considerations, recruitment concerns and issues related to data collection and randomization to treatment groups. Management and monitoring of data, as well as quality assurance procedures are described. Finally, a real world perspective is shared from a recently conducted multisite randomized clinical trial of reflexology for women diagnosed with advanced breast cancer. RESULTS: The use of multiple sites in the conduct of CAM-based randomized clinical trials can provide an efficient, collaborative and robust approach to study coordination and data collection that maximizes efficiency and ensures the quality of results. CONCLUSIONS: Multisite randomized clinical trial designs can offer the field of CAM research a more standardized and efficient approach to examine the effectiveness of novel therapies and treatments. Special attention must be given to intervention fidelity, consistent data collection and ensuring data quality. Assessment and reporting of quantitative indicators of data quality should be required.

Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks' gestation.

BACKGROUND: Transiently low levels of thyroid hormones occur in approximately 50% of neonates born 24-28 weeks' gestation and are associated with higher rates of cerebral palsy and cognitive impairment. Raising hormone levels shows promise for improving neurodevelopmental outcome. OBJECTIVE: To identify whether any of 4 thyroid hormone supplementation regimens could raise T(4) and FT(4) without suppressing TSH (biochemical euthyroidism). METHODS: Eligible subjects had gestational ages between 24 07 and 2767 weeks and were randomized <24 hours of birth to one of six study arms (n = 20-27 per arm): placebo (vehicle: 5% dextrose), potassium iodide (30 microg/kg/d) and continuous or bolus daily infusions of either 4 or 8 microg/kg/d of T(4) for 42 days. T(4) was accompanied by 1 microg/kg/d T(3) during the first 14 postnatal days and infused with 1 mg/mL albumin to prevent adherence to plastic tubing. RESULTS: FT(4) was elevated in the first 7 days in all hormone-treated subjects; however, only the continuous 8 microg/kg/d treatment arm showed a significant elevation in all treatment epochs (P < .002 versus all other groups). TT(4) remained elevated in the first 7 days in all hormone-treated subjects (P < .05 versus placebo or iodine arms). After 14 days, both 8 microg/kg/d arms as well as the continuous 4 microg/kg/d arm produced a sustained elevation of the mean and median TT(4), >7 microg/dL (90 nM/L; P < .002 versus placebo). The least suppression of THS was achieved in the 4 microg/kg/d T(4) continuous infusion arm. Although not pre-hypothesized, the duration of mechanical ventilation was significantly lower in the continuous 4 microg/kg/d T(4) arm and in the 8 microg/kg/d T(4) bolus arm (P < .05 versus remaining arms). ROP was significantly lower in the combined 4 thyroid hormone treatment arms than in the combined placebo and iodine arms (P < .04). NEC was higher in the combined 8 microg/kg/d arms (P < .05 versus other arms). CONCLUSIONS: Elevation of TT(4) with only modest suppression of TSH was associated with trends suggesting clinical benefits using a continuous supplement of low-dose thyroid hormone (4 microg/kg/d) for 42 days. Future trials will be needed to assess the long-term neurodevelopmental effects of such supplementation.

Health service utilization for perceived postpartum morbidity among poor women living in Karachi.

To explore traditional beliefs and practices, to assess puerperal morbidity, and to understand care-seeking behaviors, a qualitative and quantitative study was conducted in low socio-economic settlements of Karachi, Pakistan. Five focus group discussions and 15 in-depth interviews were conducted in July and August 2000. 525 Muslim women, who were 6-8 weeks post-partum, were then interviewed at home. Maternal care was relatively good-more than three-quarters of recent mothers sought antenatal care and more than half (267/525) delivered in a hospital or maternity home. Counseling to attend post-partum clinics among facility deliveries was 16% (43/267), of which only 26% (11/43) attended. Practices during the delivery and puerperium, such as massaging the vaginal walls with mustard oil during labor to facilitate delivery and inserting vaginal or rectal herbal pessaries to facilitate 'shrinkage of the uterus' and/or 'strengthening of the backbone', were pervasive. The core symptoms that are clinically significant during the puerperium are heavy vaginal bleeding and high fever, since they are potentially fatal symptoms if appropriate and timely care is not sought. About half of the study women (53.3%) reported at least one illness symptom, high fever (21.1%), heavy vaginal bleeding (13.9%), and foul smelling vaginal discharge (9.6%). Women did not know the underlying biologic cause of their perceived post-partum morbidity; weakness was frequently mentioned. Women sought care initially from close relatives or traditional healers and if they continued to suffer from their morbidity they finally approached a trained health care (allopathic) provider. The high prevalence of perceived post-partum morbidity illustrates the demand for post-partum community-based health care programs. We suggest promoting maternal health education that encourages women to seek appropriate and timely care by accessing public or private health services.