Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.

Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.

Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naïve HIV-1-positive individuals: 96 week results from FLAMINGO.

INTRODUCTION: Dolutegravir (DTG) 50 mg once daily was superior to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL (p=0.025) [1]. We present data through Week 96. MATERIAL AND METHODS: FLAMINGO is a multicentre, randomized, open-label, Phase IIIb non-inferiority study, in which HIV-1-positive ART-naïve adults with HIV-1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator-selected backbone NRTIs (TDF/FTC or ABC/3TC). Participants were stratified by screening HIV-1 RNA (≤100K c/mL) and NRTI backbone. RESULTS: A total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002). Secondary analyses supported primary results: per-protocol [(DTG 83% vs. DRV/r 70%), 95% CI 12.9 (5.3, 20.6)] and treatment-related discontinuation = failure [(98% vs. 95%), 95% CI 3.2 (-0.3, 6.7)]. Overall virologic non-response (DTG 8%; DRV/r 12%) and non-response due to other reasons (DTG 12%; DRV/r 21%) occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96) and in the TDF/FTC stratum (79% vs. 64%); consistent responses were seen in the ABC/3TC stratum (82% vs. 75%). Six participants (DTG 2, none post-Week 48; DRV/r 4, two post-Week 48) experienced protocol-defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24); none had treatment-emergent resistance to study drugs. Most frequent drug-related adverse events (AEs) were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24%) than DTG (10%). Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22%) vs. DTG (7%), p<0.001; mean changes in creatinine for DTG (~0.18 mg/dL) observed at Week 2 were stable through Week 96. CONCLUSIONS: Once-daily DTG was superior to once-daily DRV/r in treatment-naïve HIV-1-positive individuals, with no evidence of emergent resistance to DTG in virologic failure and relatively similar safety profiles for DTG and DRV/r through 96 Weeks.

Intralesional adenovirus-mediated interleukin-2 gene transfer for advanced solid cancers and melanoma.

Numerous preclinical and clinical studies have shown that interleukin-2 (IL-2) induces regression of metastatic tumors. We have conducted a phase I/II, multicenter, open-label, dose-escalating study to evaluate the safety, efficacy, and biological effects of repeated intratumoral injections of adenovirus-IL-2 (TG1024) in patients with advanced solid tumors and melanoma. Thirty five patients (twenty-five with metastatic melanoma and ten with other solid tumors) were treated in eight successive cohorts at dose levels ranging from 3 x 10(8) to 3 x 10(11) viral particles (vp). Intratumoral TG1024 injections in combination with dacarbazine (DTIC) were tested in metastatic melanoma in one cohort. No clinical responses were observed at doses below 3 x 10(11) vp. Six local objective responses were recorded in patients receiving 3 x 10(11) vp per treatment [five in metastatic melanoma and one in metastatic squamous cell carcinoma (SCC) of the skin], of which two were complete responses (CRs). Most of the common side effects were injection site reactions and flu-like syndrome. TG1024 dose intensification across cohorts resulted in increased serum IL-2 levels after the injection. Intratumoral TG1024 injection induced pronounced inflammation of the treated lesion, with predominant CD8(+), TIA+ lymphocytic infiltrate. Our results show that intratumoral injections of TG1024 are safe and well tolerated. The clinical activity of TG1024 observed in this study warrants further investigations.

Pharmacologic profile of UR-7247, an orally active angiotensin II AT1 receptor antagonist, in healthy volunteers. p6.

This study was conducted to assess the pharmacologic properties of the new orally active angiotensin II subtype I (AT1) antagonist UR-7247, a product with a half-life >100 h in humans. The experiment was designed as an open-label, single-dose administration study with four parallel groups of four healthy men receiving increasing single oral doses (2.5, 5, and 10 mg) of UR-7247 or losartan, 100 mg. Angiotensin II receptor blockade was investigated < or =96 h after drug intake, with three independent methods [i.e., the inhibition of blood pressure (BP) response to exogenous Ang II, an in vitro Ang II-receptor assay (RRA), and the reactive increase in plasma angiotensin II. Plasma drug levels also were measured. The degree of blockade observed in vivo was statistically significant < or = 96 h with all UR-7247 doses for diastolic BP (p < 0.05) and < or =48 h for systolic BP. The maximal inhibition achieved with 10 mg UR-7247 was measured 6-24 h after drug intake and reached 54 +/- 17% and 48 +/- 20% for diastolic and systolic responses, respectively. Losartan, 100 mg, induced a greater short-term AT1-receptor blockade than 2.5- and 5.0-mg doses of UR-7247 (p < 0.001 for diastolic BP), but the UR-7247 effect was longer lasting. In vivo, no significant difference was observed between 10 mg UR-7247 and 100 mg losartan 4 h after drug intake, but in vitro, the blockade achieved with 100 mg losartan was higher than that seen with UR-7247. Finally, the results confirm that UR-7247 has a very long plasma elimination half-life, which may be due to a high but also tight binding to protein binding sites. In conclusion, UR-7247 is a long-lasting, well-tolerated AT1 receptor in healthy subjects.

A Novel Acute Retroviral Syndrome Severity Score Predicts the Key Surrogate Markers for HIV-1 Disease Progression.

OBJECTIVE: Best long-term practice in primary HIV-1 infection (PHI) remains unknown for the individual. A risk-based scoring system associated with surrogate markers of HIV-1 disease progression could be helpful to stratify patients with PHI at highest risk for HIV-1 disease progression. METHODS: We prospectively enrolled 290 individuals with well-documented PHI in the Zurich Primary HIV-1 Infection Study, an open-label, non-randomized, observational, single-center study. Patients could choose to undergo early antiretroviral treatment (eART) and stop it after one year of undetectable viremia, to go on with treatment indefinitely, or to defer treatment. For each patient we calculated an a priori defined "Acute Retroviral Syndrome Severity Score" (ARSSS), consisting of clinical and basic laboratory variables, ranging from zero to ten points. We used linear regression models to assess the association between ARSSS and log baseline viral load (VL), baseline CD4+ cell count, and log viral setpoint (sVL) (i.e. VL measured ≥90 days after infection or treatment interruption). RESULTS: Mean ARSSS was 2.89. CD4+ cell count at baseline was negatively correlated with ARSSS (p = 0.03, n = 289), whereas HIV-RNA levels at baseline showed a strong positive correlation with ARSSS (p<0.001, n = 290). In the regression models, a 1-point increase in the score corresponded to a 0.10 log increase in baseline VL and a CD4+cell count decline of 12/µl, respectively. In patients with PHI and not undergoing eART, higher ARSSS were significantly associated with higher sVL (p = 0.029, n = 64). In contrast, in patients undergoing eART with subsequent structured treatment interruption, no correlation was found between sVL and ARSSS (p = 0.28, n = 40). CONCLUSION: The ARSSS is a simple clinical score that correlates with the best-validated surrogate markers of HIV-1 disease progression. In regions where ART is not universally available and eART is not standard this score may help identifying patients who will profit the most from early antiretroviral therapy.

Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.

Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

Long-Term Safety of Canakinumab in Patients with Gouty Arthritis.

Background/Purpose: Gouty arthritis (GA) is a chronic inflammatory disease. Targeting the inflammatory pathway through IL-1_ inhibition with canakinumab (CAN) may provide significant long-term benefits. CAN safety versus triamcinolone acetonide (TA) over initial 24 weeks (blinded study) for patients (pts) with history of frequent attacks (_3 in year before baseline) was reported earlier from core (_-RELIEVED [_-REL] and _-REL-II) and first extension (E1) studies1. Herein we present full 18-month long-term CAN safety data, including open-label second extension (E2) studies. Methods: GA pts completing _-REL E1 and _-REL-II E1 studies1 were enrolled in these 1-year, open-label, E2 studies. All pts entering E2, whether randomized to CAN or TA, received CAN 150 mg sc on demand upon new attack. Data are presented only for pts randomized to CAN, and are reported cumulatively, i.e. including corresponding data from previously reported core and E1 studies. Long-term safety outcomes and safety upon re-treatment are presented as incidence rate per 100 patient-years (pyr) of study participation for AEs and SAEs. Deaths are reported for all pts (randomized to CAN or TA). Selected predefined notable laboratory abnormalities are shown (neutrophils, platelets, liver and renal function tests). Long-term attack rate per year is also provided. Results: In total, 69/115 (60%) and 72/112 (64.3%) of the pts randomized to CAN in the two core studies entered the two E2 studies, of which 68 and 64 pts, respectively completed the E2 studies. The 2 study populations had differing baseline comorbidity and geographic origin. Lab data (not time adjusted) for neutropenia appears worse after retreatment in _-REL E2, and deterioration of creatinine clearance appears worse after retreatment (Table 1). The time-adjusted incidence rates for AEs were 302.4/100 pyr and 360/100 pyr, and for SAEs were 27.9/100 pyr and 13.9/100 pyr in _-REL E2 and _-REL-II E2 respectively (Table 1). The time-adjusted incidence rates of any AEs, infection AEs, any SAEs, and selected SAEs before and after re-treatment are presented in Table 1. Incidence rates for AEs and SAEs declined after re-treatment, with the exception of SAEs in _-REL-II E2, which increased from 2.9/100 pyr to 10.9/100 pyr (no infection SAEs after retreatment in _-REL-II E2, and other SAEs fit no special pattern). In the total safety population (N_454, core and all extensions), there were 4 deaths, 2 in the core studies previously reported1 and 2 during the _-REL E2 study (one patient in the CAN group died from pneumonia; one patient in the TA group who never received CAN died of pneumococcal sepsis). None of the deaths was suspected by investigators to be study drug related. The mean rates of new attacks per year on CAN were 1.21 and 1.18 in _-REL E2 and in _-REL-II E2. Conclusion: The clinical safety profile of CAN upon re-treatment was maintained long-term with no new infection concerns

Rituximab treatment in non-malignant inflammatory sensory polyganglionopathy

Non-malignant inflammatory sensory polyganglionopathy (NISP) is the most common form of acquired ganglionopathies, a rare and distinct subgroup of peripheral nerve diseases characterized by a primary degeneration of sensory neurons in dorsal root ganglia. There is a rational for the use of immune modifying agents (IMA) in NISP since an underlying auto-immune process is demonstrated or suspected. However, commonly used IMA such as corticosteroids, azathioprine, methotrexate or IVIG do not prevent disease's progression in the majority of patients. The use of newer IMA, especially those directed against B-cells, may be a therapeutic alternative. An interesting candidate is rituximab, a mouse-human chimeric anti CD20 antibody that specifically eliminates B-cells and B-cells precursors.Objectives: This is a prospective open label pilot study to determine the efficacy of rituximab treatment in NISP patients, who did not respond to commonly used IMA.Methods: Five patients (40% male) with a mean age of 55 years (range 49-67), diagnosed with NISP after extensive work-up, were treated (schema used for one cure: 2 9 1gr within 15 days interval). Neurological scores (NIS, ISSS, ODSS) and B cell counts were assessed at baseline and during clinical follow-up at 2 and 6 monthsto assess treatment efficacy.Results: The treatment was generally well tolerated. Minor adverse events reported were transient arterial hypotension during the infusions in two patients and intermittent mild leucopenia in one patient. Clinical evolution during the follow-up period was characterized by a stability of the functional scores in four patients (80%) and the continuation of disability progression of one patient (20%). CD4 cells disappeared in all patients after the second infusion, an effect that lasted until the follow up at 6 months.Conclusion: The preliminary results of this pilot study indicate that rituximab is generally well tolerated and prevents progression of disability during the 6-month observation period in NISP patients. Inclusion of additional patients and extending of the follow-up period are intended to further investigate the efficacy of rituximab in NISP.

Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study.

Objective The goal of this study was to investigate whether increasing the dose of an angiotensin II receptor blocker (ARB) provides as much benefits as combining the ARB with an angiotensin-converting enzyme inhibitor (ACEI) in terms of blood pressure (BP) control and urinary albumin excretion (UAE) in hypertensive patients with a proteinuria.Methods We enrolled 20 hypertensive patients with proteinuric nephropathies and a reduced renal function in a randomized, 12-month, triple-crossover, prospective, open-label study to compare the effects of a regular dose of losartan (Los 100mg q.d., LOS100) vs. a high dose of losartan (Los 100mg b.i.d., LOS200) vs. losartan 100mg q.d. associated with lisinopril 20 mg q.d. (LOS100 + LIS20). Each treatment was given for 8 weeks with a 4-week initial run-in period and 2 weeks of washout between each treatment phases. 24 h UAE and ambulatory BP were measured during the running phase and at the end of each treatment period.Results Compared to pretreatment, 24 h SBP and DBP were reduced by 10/5 +/- 7/4 mmHg with LOS100 (P=0.023 vs. baseline) and, respectively, 13/6 +/- 12/5 mmHg with LOS200 (P=0.011) and 19/9 +/- 15/8 mmHg with LOS100+LIS20 (P < 0.01). UAE decreased significantly with LOS100 and to an even greater degree with LOS200 and LOS100+LIS20 (P < 0.01 vs. baseline for both and P=0.032, LOS100+LIS20 vs. LOS200). The combination had a greater impact in patients with a high baseline proteinuria as suggested by a nonparallel leftward shift of the relationship between the changes in UAE induced by the combination and those induced by LOS200. The high dose of losartan was better tolerated than the combination.Conclusion Increasing the dose of losartan from 100mg once daily to 100mg twice a day enables to obtain a greater decrease in BP and proteinuria and is better tolerated than combining the ARB with lisinopril, though the high dose appears to be slightly less effective than the combination in patients with a marked proteinuria. J Hypertens 29: 1228-1235 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Long-term outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) enrolled in two prospective trials.

The purpose of this study was to assess the outcomes of 118 patients with eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in 2 prospective, randomized, open-label clinical trials (1994-2005), with or without Five-Factor Score (FFS)-defined poor-prognosis factors, focusing on survival, disease-free survival, relapses, clinical and laboratory findings, therapeutic responses, and factors predictive of relapse. Forty-four patients with FFS ≥ 1 were assigned to receive 6 or 12 cyclophosphamide pulses plus corticosteroids and the seventy-four with FFS = 0 received corticosteroids alone, with immunosuppressant adjunction when corticosteroids failed. Patients were followed (2005-2011) under routine clinical care in an extended study and data were recorded prospectively. Mean ± SD follow-up was 81.3 ± 39.6 months. Among the 118 patients studied, 29% achieved long-term remission and 10% died. Among the 115 patients achieving a first remission, 41% experienced ≥1 relapses, 26.1 ± 26.8 months after treatment onset, with 57% of relapses occurring when corticosteroid-tapering reached <10 mg/day. Treatment achieved new remissions in >90%, but relapses recurred in 38%. Overall survival was good, reaching 90% at 7 years, regardless of baseline severity. Age ≥65 years was the only factor associated with a higher risk of death during follow-up. The risk of relapse was higher for patients with anti-myeloperoxidase antibodies and lower for those with >3000 eosinophils/mm(3). Sequelae remained frequent, usually chronic asthma and peripheral neuropathy. In conclusion, EGPA patients' survival rate is very good when treatment is stratified according to the baseline FFS. Relapses are frequent, especially in patients with anti-myeloperoxidase antibodies and baseline eosinophilia <3000/mm(3).

Long term retention of retigabine in a cohort of people with drug resistant epilepsy.

PURPOSE: To assess the utility of retigabine (RTG) for epilepsy in clinical practice at a single UK tertiary centre. METHODS: We identified all individuals who were offered RTG from April 2011 to May 2013. We collected demographics, seizure types, previous and current antiepileptic drugs (AEDs), starting and maximum attained daily dose of RTG, clinical benefits, side effects, and reason to discontinue RTG from in- and outpatient encounters until February 28, 2014. RESULTS: 145 people who had failed a median of 11 AEDs took at least one dose of RTG. One year retention was 32% and decreased following the safety alert by the US Federal Drug Administration (FDA) in April 2013. None became seizure free. 34 people (24%) reported a benefit that was ongoing at last assessment in five (3%). The most relevant benefit was the significant reduction or cessation of drop attacks or seizure-related falls in four women, this persisted at last assessment in two. The presence of simple partial seizures was associated with longer retention, as was a higher attained dose of RTG. Adverse effects were seen in 74% and largely CNS-related or nonspecific and affected the genitourinary system in 13%. CONCLUSION: Retention of RTG was less favourable compared to data from open label extension studies of the regulatory trials. In comparison with historical data on similar retention audits retention of RTG at one year appears to be less than lamotrigine, topiramate, levetiracetam, pregabalin, zonisamide, and lacosamide, and slightly higher than gabapentin.

Residual venous obstruction, alone and in combination with D-dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the prolong study.

OBJECTIVE: This study aims to assess the predictive value of residual venous obstruction (RVO) for recurrent venous thrombo-embolism (VTE) in a study using D-dimer to predict outcome. DESIGN: This is a multicentre randomised open-label study. METHODS: Patients with a first episode of idiopathic VTE were enrolled on the day of anticoagulation discontinuation when RVO was determined by compression ultrasonography in those with proximal deep vein thrombosis (DVT) of the lower limbs. D-dimer was measured after 1 month. Patients with normal D-dimer did not resume anticoagulation while patients with abnormal D-dimer were randomised to resume anticoagulation or not. The primary outcome measure was recurrent VTE over an 18-month follow-up. RESULTS: A total of 490 DVT patients were analysed (after excluding 19 for different reasons and 118 for isolated pulmonary embolism (PE)). Recurrent DVT occurred in 19% (19/99) of patients with abnormal D-dimer who did not resume anticoagulation and 10% (31/310) in subjects with normal D-dimer (adjusted hazard ratio: 2.1; p = 0.02). Recurrences were similar in subjects either with (11%, 17/151) or without RVO (13%, 32/246). Recurrent DVT rates were also similar for normal D-dimer, with or without RVO, and for abnormal D-dimer, with or without RVO. CONCLUSIONS: Elevated D-dimer at 1 month after anticoagulation withdrawal is a risk factor for recurrence, while RVO at the time of anticoagulation withdrawal is not.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.