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.

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke.

BACKGROUND: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. METHODS/DESIGN: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. DISCUSSION: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. TRIAL REGISTRATION: ISRCTN99643613 assigned on 4 December 2009.

Vitamin D deficiency and coronary artery disease: a review of the evidence.

Coronary artery disease remains the leading cause of death in developed countries despite significant progress in primary prevention and treatment strategies. Older patients are at particularly high risk of poor outcomes following acute coronary syndrome and impaired nutrition, including low vitamin D levels, may play a role. The extraskeletal effects of vitamin D, in particular, its role in maintaining a healthy cardiovascular system are receiving increased attention. Longitudinal studies have demonstrated increased cardiovascular mortality and morbidity associated with vitamin D deficiency. Low vitamin D levels have been linked to inflammation, higher coronary artery calcium scores, impaired endothelial function and increased vascular stiffness. However, so far, few randomized controlled trials have investigated the potential benefits of vitamin D supplementation in preventing cardiovascular events, and most available trials have tested low doses of supplementation in relatively low-risk populations. Whether vitamin D supplementation will be beneficial among patients with coronary artery disease, including high risk older patients presenting with acute coronary syndrome, is unknown and warrants further investigation.

A systematic review of fish-oil supplements for the prevention and treatment of hypertension.

AIMS: Fish oils are widely believed to promote cardiovascular health by lowering blood pressure (BP) but the evidence supporting this is not conclusive. We aimed to systematically review existing evidence. METHOD: We undertook a systematic review of randomized controlled trials and crossover trials that evaluated the effectiveness of fish-oil supplements. We included trials enrolling adults who were given fish-oil supplements with at least 8 weeks' follow up. Effects on systolic and diastolic BP were assessed using meta-analysis. Meta-regression was undertaken to explore the relationship between dose of fish oil and BP outcomes. RESULTS: We included 17 studies, with a total of 1524 participants. We explored the effects of fish-oil supplements in both normotensive and hypertensive participants with BP 140/85 mmHg at least. Meta-analyses were performed using the inverse-variance method. Data from eight studies in hypertensive participants found a statistically significant reduction in systolic and diastolic BP; 2.56 mmHg (95% CI 0.58 to 4.53) and 1.47 mmHg (95% CI 0.41 to 2.53), respectively. Nine studies in normotensive participants showed a non-significant reduction in both systolic and diastolic BP. Meta-regression showed no significant relationship between dose of fish oil and the effect on BP. CONCLUSION: The small but statistically significant effects of fish-oil supplements in hypertensive participants in this review have important implications for population health and lowering the risk of stroke and ischaemic heart disease. Their modest effects, however, mean that they should not be recommended as an alternative to BP-lowering drugs where guidelines recommend treatment.

Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset.

BACKGROUND AND PURPOSE: Antiplatelets (APs) may increase the risk of symptomatic intracerebral hemorrhage (ICH) following intravenous thrombolysis after ischemic stroke. METHODS: We assessed the safety of thrombolysis under APs in 11,865 patients compliant with the European license criteria and recorded between 2002 and 2007 in the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register (SITS-ISTR). Outcome measures of univariable and multivariable analyses included symptomatic ICH (SICH) per SITS Monitoring Study (SITS-MOST [deterioration in National Institutes of Health Stroke Scale >or=4 plus ICH type 2 within 24 hours]), per European Cooperative Acute Stroke Study II (ECASS II [deterioration in National Institutes of Health Stroke Scale >or=4 plus any ICH]), functional outcome at 3 months and mortality. RESULTS: A total of 3782 (31.9%) patients had received 1 or 2 AP drugs at baseline: 3016 (25.4%) acetylsalicylic acid (ASA), 243 (2.0%) clopidogrel, 175 (1.5%) ASA and dipyridamole, 151 (1.3%) ASA and clopidogrel, and 197 (1.7%) others. Patients receiving APs were 5 years older and had more risk factors than AP naïve patients. Incidences of SICH per SITS-MOST (ECASS II respectively) were as follows: 1.1% (4.1%) AP naïve, 2.5% (6.2%) any AP, 2.5% (5.9%) ASA, 1.7% (4.2%) clopidogrel, 2.3% (5.9%) ASA and dipyridamole, and 4.1% (13.4%) ASA and clopidogrel. In multivariable analyses, the combination of ASA and clopidogrel was associated with increased risk for SICH per ECASS II (odds ratio, 2.11; 95% CI, 1.29 to 3.45; P=0.003). However, we found no significant increase in the risk for mortality or poor functional outcome, irrespective of the AP subgroup or SICH definition. CONCLUSIONS: The absolute excess of SICH of 1.4% (2.1%) in the pooled AP group is small compared with the benefit of thrombolysis seen in randomized trials. Although caution is warranted in patients receiving the combination of ASA and clopidogrel, AP treatment should not be considered a contraindication to thrombolysis.

Relaxation therapies for the management of primary hypertension in adults.

BACKGROUND: Lifestyle interventions are often recommended as initial treatment for mild hypertension, but the efficacy of relaxation therapies is unclear. OBJECTIVES: To evaluate the effects of relaxation therapies on cardiovascular outcomes and blood pressure in people with elevated blood pressure. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. INCLUSION CRITERIA: RCTs of a parallel design comparing relaxation therapies with no active treatment, or sham therapy; follow-up >/=8 weeks; participants over 18 years, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg); SBP and DBP reported at end of follow-up. EXCLUSION CRITERIA: participants were pregnant; participants received antihypertensive medication which changed during the trial. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: 29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I(2) =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I(2) =63%). AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.

Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials.

PURPOSE: To quantify effectiveness of lifestyle interventions for hypertension. DATA SOURCES: Electronic bibliographic databases from 1998 onwards, existing guidelines, systematic reviews. STUDY SELECTION AND DATA ABSTRACTION: We included randomized, controlled trials with at least 8 weeks' follow-up, comparing lifestyle with control interventions, enrolling adults with blood pressure at least 140/85 mmHg. Primary outcome measures were systolic and diastolic blood pressure. Two independent reviewers selected trials and abstracted data; differences were resolved by discussion. RESULTS: We categorized trials by type of intervention and used random effects meta-analysis to combine mean differences between endpoint blood pressure in treatment and control groups in 105 trials randomizing 6805 participants. Robust statistically significant effects were found for improved diet, aerobic exercise, alcohol and sodium restriction, and fish oil supplements: mean reductions in systolic blood pressure of 5.0 mmHg [95% confidence interval (CI): 3.1-7.0], 4.6 mmHg (95% CI: 2.0-7.1), 3.8 mmHg (95% CI: 1.4-6.1), 3.6 mmHg (95% CI: 2.5-4.6) and 2.3 mmHg (95% CI: 0.2-4.3), respectively, with corresponding reductions in diastolic blood pressure. Relaxation significantly reduced blood pressure only when compared with non-intervention controls. We found no robust evidence of any important effect on blood pressure of potassium, magnesium or calcium supplements. CONCLUSIONS: Patients with elevated blood pressure should follow a weight-reducing diet, take regular exercise, and restrict alcohol and salt intake. Available evidence does not support relaxation therapies, calcium, magnesium or potassium supplements to reduce blood pressure.