Acute phase results from STORM, a multicountry observational study of bipolar disorder treatment and outcomes.

OBJECTIVES: This prospective observational study examined the outcomes associated with the treatment of bipolar mania in clinical practice settings in a diverse range of countries: Bosnia, Slovenia, Slovakia, Egypt, Saudi Arabia and Turkey. Particular emphasis was placed on investigating outcomes associated with treatment regimens including and excluding the atypical antipsychotic olanzapine. SUBJECTS AND METHODS: In- and outpatients initiating or changing oral medication for the treatment of bipolar mania were grouped into two treatment cohorts: (1) olanzapine (N=569), and (2) non-olanzapine (N=325). Clinical outcome measures included change in Clinical Global Impressions-Bipolar Version Severity of Illness scale (CGI-BP), Young Mania Rating Scale (YMRS) and Hamilton Depression Rating scale- 5 item (HAMD-5) scores, and response and remission rates. Outcomes were analysed by conventional linear or logistic regression, adjusted for potential confounders, using last observation carried forward (LOCF) at endpoint, and a marginal structural model (MSM) approach to account for treatment switching. Results from the 12-week acute phase are presented. RESULTS: Clinical improvements were observed in both cohorts. While no marked differences were apparent between the groups in adjusted mean baseline to LOCF endpoint change, longitudinal analysis of these variables using MSM averaged over all visits indicated greater improvements in the olanzapine versus non-olanzapine cohort in CGI-BP Overall (-0.26, p<0.001), CGI-BP Mania (-0.19, p<0.001), CGI-BP Depression (-0.10, p=0.003), CGI Psychosis (-0.14, p=0.001), YMRS (-1.70, p<0.001), and HAMD-5 (-0.40, p<0.001) scores. CONCLUSIONS: Inclusion of olanzapine after initiating or switching treatment for bipolar mania appeared to be beneficial during treatment in terms of symptom improvement.

Low-density lipoprotein particles and risk of intracerebral haemorrhage in subjects with cerebrovascular disease.

BACKGROUND: Only limited data are available for risk factors for intracerebral haemorrhage (ICH) in subjects with established cerebrovascular disease. DESIGN: We performed a nested case-control study of participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). This was a randomized, placebo-controlled trial that established the beneficial effects of blood pressure lowering in 6105 patients with cerebrovascular disease. METHODS: Each of 41 subjects who experienced ICH during a mean follow-up of 3.9 years was matched to 1-3 control subjects. Lipoprotein particles and other plasma markers were measured in baseline blood samples from PROGRESS participants. RESULTS: In comparison with control subjects, ICH cases had increased mean low-density lipoprotein (LDL) diameter (P=0.04) and increased large LDL particle concentration (P=0.03). The odds ratio (adjusted for regression dilution bias) for ICH risk with 10 mmHg increase in systolic blood pressure (SBP) was 1.45 (95% confidence interval: 1.01-2.09, P=0.05), with a 1 nm increase in mean LDL diameter it was 2.15 (95% confidence interval: 0.97-4.77, P=0.06), and with 100 nmol/l increase in large LDL particle concentration it was 1.18 (95% confidence interval: 0.98-1.43, P=0.08). Plasma levels of C-reactive protein (CRP), soluble vascular cell adhesion molecule 1 (sVCAM-1), homocysteine, amino-terminal-pro-B-type natriuretic peptide (NT-proBNP), and renin were not associated with ICH risk. CONCLUSION: SBP predicted ICH risk in subjects with cerebrovascular disease, whereas CRP, sVCAM-1, homocysteine, NT-proBNP, and renin did not predict ICH risk. The trends for prediction of ICH risk by mean LDL particle diameter and large LDL particle concentration are hypothesis generating and require confirmation in larger studies.

Once-daily duloxetine 60 mg in the treatment of major depressive disorder: multicenter, double-blind, randomized, paroxetine-controlled, non-inferiority trial in China, Korea, Taiwan and Brazil.

The aim of the present paper was to compare the efficacy and safety of duloxetine with paroxetine in the acute treatment of major depressive disorder (MDD). In a randomized, double-blind trial of 8 weeks active treatment, patients with non-psychotic MDD were randomized to duloxetine 60 mg (n = 238) or paroxetine 20 mg (n = 240) once daily. Efficacy was primarily measured on change in the 17-item Hamilton Rating Scale for Depression (HAMD(17)) using a non-inferiority test with a margin of 2.2. Secondary efficacy measures included the HAMD(17) subscales, Hamilton Rating Scale for Anxiety, Clinical Global Impressions-Severity, Patient Global Impressions-Improvement, Somatic Symptoms Inventory and Visual Analog Scales (VAS) for pain. Safety measures included treatment-emergent adverse events (TEAE), vital signs, weight, laboratory analyses and electrocardiograms. Non-inferiority of duloxetine to paroxetine was demonstrated because the upper bound of the confidence interval for mean difference in HAMD(17) change (0.71) was less than the non-inferiority margin. Secondary efficacy end-points did not differ significantly between treatments with the exception of VAS back pain, where the pooled mean was lower in the duloxetine group (17.1) compared with the paroxetine group (20.3, P = 0.048). No significant differences were observed in the number of early discontinuations and overall TEAE. However, significantly greater proportions of patients in the duloxetine group experienced nausea and palpitations. No clinically relevant changes in laboratory values, vital signs, weight or electrocardiograms were observed with either treatment. The present study verifies the utility of duloxetine as an efficacious and safe treatment for both emotional and physical symptoms of MDD in this predominantly Asian patient sample.

Perindopril-based blood pressure-lowering therapy reduces amino-terminal-pro-B-type natriuretic peptide in individuals with cerebrovascular disease.

OBJECTIVE: The plasma amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) level predicted congestive heart failure, myocardial infarction, and ischaemic stroke in participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of the effects of blood pressure lowering on cardiovascular events among individuals with cerebrovascular disease. Active treatment comprised a flexible regimen based on perindopril, with the addition of indapamide at the discretion of treating physicians. Active treatment reduced cardiovascular events, and we therefore investigated whether active treatment modified NT-proBNP and other cardiovascular risk factors. METHODS: We measured NT-proBNP and other cardiovascular risk factors at randomization and after 13 months of therapy in a subset of 357 PROGRESS participants. RESULTS: Baseline systolic and pulse pressures were higher in individuals with elevated baseline NT-proBNP levels. In comparison with placebo, active treatment reduced the blood pressure and NT-proBNP levels, and increased renin levels. Reduction of NT-proBNP levels by active treatment was most evident in individuals with baseline NT-proBNP levels in the highest quarter (> 26 pmol/l), with a median reduction of 16 pmol/l (interquartile range 0-51 pmol/l, P = 0.004), corresponding to a median decrease of 39% (interquartile range 0-69%). Active treatment reduced blood pressure similarly for individuals in each of the four quarters of baseline NT-proBNP. Active therapy had no effect on plasma lipid, C-reactive protein, homocysteine, or soluble vascular cell adhesion molecule 1 levels. CONCLUSION: We conclude that plasma NT-proBNP level, in addition to predicting cardiovascular risk, may provide a measure of risk reduction by blood pressure-lowering therapy.

Soluble vascular cell adhesion molecule 1 and N-terminal pro-B-type natriuretic peptide in predicting ischemic stroke in patients with cerebrovascular disease.

BACKGROUND: Patients with stroke or transient ischemic attack are at high risk of another stroke, and there is need for improved strategies to predict recurrent stroke. OBJECTIVE: To assess the prognostic value of levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein, homocysteine, renin, and lipids and lipoprotein particle concentration and size in patients with previous stroke or transient ischemic attack. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study of participants of the Perindopril Protection Against Recurrent Stroke Study was performed. The Perindopril Protection Against Recurrent Stroke Study was a placebo-controlled trial of a perindopril erbumine-based, blood pressure-lowering regimen that reduced ischemic stroke risk by 24% among individuals with previous stroke or transient ischemic attack. Each of 252 patients who experienced ischemic stroke during a mean follow-up of 3.9 years was matched to 1 to 3 control patients. Matching variables were age, sex, treatment allocated, region, and most recent qualifying event at randomization. MAIN OUTCOME MEASURES: Risk of ischemic stroke predicted by baseline levels of sVCAM-1, NT-proBNP, C-reactive protein, homocysteine, renin, and lipids and lipoprotein particle concentration and size. RESULTS: Levels of sVCAM-1 and NT-proBNP predicted recurrent ischemic stroke. The odds ratio for patients in the highest, as compared with the lowest, quarter was 2.24 (95% confidence interval, 1.35-3.73) for sVCAM-1 level and 1.62 (95% confidence interval, 0.98-2.69) for NT-proBNP level, after adjustment for matching and other risk factors. Patients in the highest quarters for both sVCAM-1 and NT-proBNP levels had 3.6 times the risk of recurrent ischemic stroke compared with patients in the lowest quarters for both biologic markers. Level of sVCAM-1 was similarly predictive of ischemic stroke in patients allocated to placebo and perindopril-based therapy. Baseline plasma levels of C-reactive protein, homocysteine, renin, and lipids and lipoprotein particle concentration and size did not predict recurrent ischemic stroke risk. CONCLUSION: Measurement of sVCAM-1 and NT-proBNP levels provides prognostic information for recurrent ischemic stroke beyond traditional risk factors.

Prediction of myocardial infarction by N-terminal-pro-B-type natriuretic peptide, C-reactive protein, and renin in subjects with cerebrovascular disease.

BACKGROUND: B-type natriuretic peptide (BNP), C-reactive protein (CRP), and renin are elevated in persons at risk for cardiovascular disease. However, data that directly compare these markers in the prediction of myocardial infarction (MI) are limited. METHODS AND RESULTS: N-terminal-proBNP (NT-proBNP), CRP, and renin were measured in baseline blood samples from a nested case-control study of the 6105 participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack. Each of 206 subjects who experienced MI, either fatal or nonfatal, during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. Most MI cases (67%) occurred in subjects without a history of coronary heart disease. NT-proBNP, CRP, and renin each predicted MI; the odds ratio for subjects in the highest compared with the lowest quarter was 2.2 (95% CI, 1.3 to 3.6) for NT-proBNP, 2.2 (95% CI, 1.3 to 3.6) for CRP, and 1.7 (95% CI, 1.1 to 2.8) for renin. NT-proBNP and renin, but not CRP, remained predictors of MI after adjustment for all other predictors, including LDL and HDL cholesterol levels. Individuals with both NT-proBNP and renin in their highest quarters had 4.5 times the risk of MI compared with subjects with both biological markers in their lowest quarters. CONCLUSIONS: NT-proBNP and renin, but not CRP, are independent predictors of MI risk after stroke or transient ischemic attack, providing information additional to that provided by classic risk factors, and may enable more effective targeting of MI prevention strategies.

Prediction of heart failure by amino terminal-pro-B-type natriuretic peptide and C-reactive protein in subjects with cerebrovascular disease.

B-type natriuretic peptide (BNP) and C-reactive protein (CRP) are elevated in persons at risk for congestive heart failure (CHF). However, limited data are available directly comparing BNP-related peptides and CRP in persons at risk of CHF. To evaluate amino terminal-pro-BNP (NT-proBNP) and CRP, separately and together, for assessment of risk of CHF, we performed a nested case-control study of the 6105 participants of the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), a placebo-controlled study of a perindopril-based blood pressure-lowering regimen among individuals with previous stroke or transient ischemic attack (TIA). Each of 258 subjects who developed CHF resulting in death, hospitalization, or withdrawal of randomized therapy during a mean follow-up of 3.9 years was matched to 1 to 3 control subjects. NT-proBNP and CRP predicted CHF; the odds ratio for subjects in the highest compared with the lowest quarter was 4.5 (95% confidence interval, 2.7 to 7.5) for NT-proBNP and 2.9 (confidence interval, 1.9 to 4.7) for CRP, and each remained a predictor of CHF after adjustment for all other predictors. Screening for both markers provided better prognostic information than screening for either alone. Elevation of NT-proBNP above 50 pmol/L and CRP above 0.84 mg/L predicted CHF with sensitivity of 64% and specificity of 66%. NT-proBNP and CRP predicted CHF in subjects receiving perindopril-based therapy. We conclude that NT-proBNP and CRP are independent predictors of CHF risk after stroke or TIA. Moreover, NT-proBNP and CRP may be markers of mechanisms of CHF pathogenesis distinct from those responsive to angiotensin-converting enzyme inhibitor-based therapy.