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Background

The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.

The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.

Methods

Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.

Conclusion

The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.

Trial Registration

Current Controlled Trials [ISCRTN74418480]

Background

During the first days after stroke, one to two fifths of the patients develop fever or subfebrile temperatures. Body temperature is a strong prognostic factor after stroke. Pharmacological reduction of temperature in patients with acute ischaemic stroke may improve their functional outcome. Previously, we studied the effect of high dose (6 g daily) and low dose (3 g daily) paracetamol (acetaminophen) in a randomised placebo-controlled trial of 75 patients with acute ischemic stroke. In the high-dose paracetamol group, mean body temperature at 12 and 24 hours after start of treatment was 0.4°C lower than in the placebo group. The effect of ibuprofen, another potent antipyretic drug, on body-core temperature in normothermic patients has not been studied.

Aim

The aim of the present trial is to study the effects of high-dose paracetamol and ibuprofen on body temperature in patients with acute ischaemic stroke, and to study the safety of these treatments.

Design

Seventy-five (3 × 25) patients with acute ischaemic stroke confined to the anterior circulation will be randomised to treatment with either: 400 mg ibuprofen, 1000 mg acetaminophen, or with placebo 6 times daily during 5 days. Body-temperatures will be measured with a rectal electronic thermometer at the start of treatment and after 24 hours. An infrared tympanic thermometer will be used to monitor body temperature at 2-hour intervals during the first 24 hours and at 12-hour intervals thereafter. The primary outcome measure will be rectal temperature at 24 hours after the start of treatment. The study results will be analysed on an intent-to-treat basis, but an on-treatment analysis will also be performed. No formal interim analysis will be carried out.

Background

Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect.

Methods

Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter.

Results

No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period.

Conclusions

Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.

Background

Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children.

Methods

Seventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P < 0.05.

Results

A higher proportion of subjects in the intervention group (83.3%) became afebrile at 6 hours than in the control group (57.6%); P = 0.018. This difference was accentuated at 7 and 8 hours (P < 0.001) with a significantly longer time to recurrence of fever in the intervention group (mean ± SD of 7.4 ± 1.3 versus 5.7 ± 2.2 hours), P < 0.001. Odds ratios (95%CI) for defervescence were 5.6 (1.3; 23.8), 19.5 (3.5; 108.9) and 15.3 (3.4; 68.3) at 6, 7 and 8 hours respectively. Two-way ANOVA with repeated measures over time revealed a significantly larger decline in temperature in the intervention group at times 7 (P = 0.026) and 8 (P = 0.002) hours.

Conclusion

A single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.

Background

The antipyretic effectiveness of rectal versus oral acetaminophen is not well established. This study is designed to compare the antipyretic effectiveness of two rectal acetaminophen doses (15 mg/kg) and (35 mg/kg), to the standard oral dose of 15 mg/kg.

Methods

This is a randomized, double-dummy, double-blind study of 51 febrile children, receiving one of three regimens of a single acetaminophen dose: 15 mg/kg orally, 15 mg/kg rectally, or 35 mg/kg rectally. Rectal temperature was monitored at baseline and hourly for a total of six hours. The primary outcome of the study, time to maximum antipyresis, and the secondary outcome of time to temperature reduction by at least 1°C were analyzed by one-way ANOVA. Two-way ANOVA with repeated measures over time was used to compare the secondary outcome: change in temperature from baseline at times1, 2, 3, 4, 5, and 6 hours among the three groups. Intent-to-treat analysis was planned.

Results

No significant differences were found among the three groups in the time to maximum antipyresis (overall mean = 3.6 hours; 95% CI: 3.2–4.0), time to fever reduction by 1°C or the mean hourly temperature from baseline to 6 hours following dose administration. Hypothermia (temperature < 36.5°C) occurred in 11(21.6%) subjects, with the highest proportion being in the rectal high-dose group.

Conclusion

Standard (15 mg/kg) oral, (15 mg/kg) rectal, and high-dose (35 mg/kg) rectal acetaminophen have similar antipyretic effectiveness.

Summary

A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms.

Introduction

Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins’ potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion.

Methods

Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass (N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset.

Results

Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h.

Conclusions

Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion.

Background: Acetaminophen (paracetamol) is recommended as the initial pharmacological treatment for knee or hip osteoarthritis. However, survey and clinical trial data indicate greater efficacy for non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 specific inhibitors.

Design: Two randomised, double blind, placebo controlled, crossover multicentre clinical trials, Patient Preference for Placebo, Acetaminophen or Celecoxib Efficacy Studies (PACES).

Patients: Osteoarthritis of knee or hip.

Intervention: "Wash out" of treatment; randomisation; 6 weeks of celecoxib 200 mg/day, acetaminophen 1000 mg four times a day, or placebo; second "wash out;" crossover to 6 weeks of second treatment.

Measurements: Western Ontario McMaster Osteoarthritis Index (WOMAC), visual analogue pain scale, patient preference between two treatments.

Results: Celecoxib was more efficacious than acetaminophen in both periods in both studies; WOMAC and pain scale scores differed at p<0.05 in period II and both periods combined of PACES-a and in periods I and II and both periods combined in PACES-b, but not in period I of PACES-a. Acetaminophen was more efficacious than placebo, generally p<0.05 in PACES-b, and >0.05 in PACES-a. Patient preferences were 53% celecoxib v 24% acetaminophen in PACES-a (p<0.001) and 50% v 32% in PACES-b (p = 0.009); 37% acetaminophen v 28% placebo in PACES-a (p = 0.340) and 48% v 24% in PACES-b (p = 0.007). No clinically or statistically significant differences were seen in adverse events or tolerability among the three treatment groups.

Conclusions: Greater efficacy was seen for celecoxib v acetaminophen v placebo, while adverse events and tolerability were similar. Variation in results and statistical significance in the two different trials are of interest.

Objective To investigate whether paracetamol (acetaminophen) plus ibuprofen are superior to either drug alone for increasing time without fever and the relief of fever associated discomfort in febrile children managed at home.

Design Individually randomised, blinded, three arm trial.

Setting Primary care and households in England.

Participants Children aged between 6 months and 6 years with axillary temperatures of at least 37.8°C and up to 41.0°C.

Intervention Advice on physical measures to reduce temperature and the provision of, and advice to give, paracetamol plus ibuprofen, paracetamol alone, or ibuprofen alone.

Main outcome measures Primary outcomes were the time without fever (<37.2°C) in the first four hours after the first dose was given and the proportion of children reported as being normal on the discomfort scale at 48 hours. Secondary outcomes were time to first occurrence of normal temperature (fever clearance), time without fever over 24 hours, fever associated symptoms, and adverse effects.

Results On an intention to treat basis, paracetamol plus ibuprofen were superior to paracetamol for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P<0.001) and may have been as good as ibuprofen (16 minutes, −7 to 39; P=0.2). For less time with fever over 24 hours, paracetamol plus ibuprofen were superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008). Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (−3 minutes, 18 to −24; P=0.8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.

Conclusion Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours.

Trial registration Current Controlled Trials ISRCTN26362730.

Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage.

Background

N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen related acute liver failure.

Methods

In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and randomly assigned to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.

Results

A total of 173 patients received NAC (n=81) or placebo (n=92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (one-sided p=0.283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; one-sided p=0.043). The benefits of transplant-free survival appeared to be confined to the 114 patients with coma grade I–II who received NAC (52% compared with 30% for placebo; one-sided p=0.010); transplant-free survival for the 59 patients with coma grade III–IV was 9% in those given NAC and 22% in those given placebo (one-sided p=0.912). The transplantation rate was lower in the NAC group but not significantly different between groups (32% vs. 45%; p=0.093). Intravenous NAC was generally well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs. 4%; p=0.031).

Conclusions

Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation. (ClinicalTrials.gov number NCT00004467)

Background

Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose.

Methods

Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection.

Results

Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin.

Conclusions

Lower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.

Purpose

Fever occurs commonly in the critically ill patients and may adversely affect outcome. Acetaminophen is one of the most commonly utilized antipyretic agents in the intensive care unit; however, there is little evidence that it is effective in this population. The objective of this study was to analyze the antipyretic activity of acetaminophen in critically ill patients.

Materials/Methods

We performed a retrospective study of MICU and SICU patients with Systemic Inflammatory Response Syndrome (SIRS) and compared the resolution of fever in the presence and absence of acetaminophen treatment by comparing the absolute reduction in body temperature and the rate of cooling over comparable time frames in fevers that were untreated and those treated with acetaminophen.

Results

We analyzed 166 febrile episodes (body temperature >38°C) in 59 patients with SIRS without cancer, neurologic disease, or liver disease. Acetaminophen was administered for 88 of 166 fevers. Febrile episodes in which other antipyretic drugs or external cooling were administered were excluded. The response to acetaminophen was variable, but the absolute temperature reduction was slightly higher (mean 0.86 vs. 0.56°C; p = 0.0362) and the cooling rate slightly more rapid (mean 0.20 vs. 0.13°C per h; p = 0.0152) in acetaminophen-treated vs. untreated fevers. There were no obvious differences between the most and least responsive patients.

Conclusions

We conclude that acetaminophen has significant albeit modest antipyretic activity in critically ill patients.

The purpose of this study was to compare antipyretic activity and evaluate tolerability of ibuprofen and paracetamol suspension in the treatment of febrile children. It was designed as a double blind, parallel group, multiple dose study comparing ibuprofen (20 mg/kg/24 hours) with paracetamol (50 mg/kg/24 hours) given at six hourly intervals for a maximum of 12 doses. Children on paediatric wards between the ages of 0.2 and 12 years, with fever as defined by an axillary temperature > or = 37.5 degrees C, were included. The main outcome measures were: change in axillary temperature; palatability of medication; changes in irritability and clinical condition; overall efficacy at the end of treatment; and number and nature of adverse events. The mean temperature change from baseline at four hours was -1.8 degrees C and -1.6 degrees C in ibuprofen and paracetamol groups respectively. In both groups: median palatability score was 'no reaction'; median irritability score at end point was 'not irritable'; median score for change in clinical condition was 'improved'; and median score for overall efficacy was 'good effect'. The proportion of patients experiencing adverse events was similar in both groups, the majority of events having doubtful or no relationship to therapy and being mild in severity. In conclusion, ibuprofen suspension was as effective and well tolerated as paracetamol in treatment of fever in young children.

Background

Muscle injuries are one of the commonest injuries affecting athletes. It often leads to significant pain and disability causing loss of training and competition time. With current treatment, the duration to return-to-play ranges form six weeks to never, depending on injury severity. Recent researches have suggested that autologous platelet-rich plasma (PRP) injection into the injured site may hasten soft tissues healing. To-date, there has been no randomised clinical trials to evaluate the effects of PRP on muscle healing. The aim of this study is to examine the effects of autologous PRP on duration to return-to-play after muscle injury.

Methods and design

A randomised, single blind controlled trial will be conducted. Twenty-eight patients aged 18 years and above with a recent grade-2 hamstring injury will be invited to take part. Participants will be randomised to receive either autologous PRP injection with rehabilitation programme, or rehabilitation programme only. Participants will be followed up at day three of study and then weekly for 16 weeks. At each follow up visit, participants will be assessed on readiness to return-to-play using a set of criteria. The primary end-point is when participants have fulfilled the return-to-play criteria or end of 16 weeks.

The main outcome measure of this study is the duration to return-to-play after injury.

Conclusion

This study protocol proposes a rigorous and potential significant evaluation of PRP use for grade-2 hamstring injury. If proven effective such findings could be of great benefit for patients with similar injuries.

Trial registration

Current Controlled Trials ISCRTN66528592

Background

The current guidelines for treatment of malaria include paracetamol to children with fever. No convincing evidence for the beneficial effects of this practice exists. Studies show that time to parasite clearance is significantly longer in children treated with paracetamol, which questions the policy. Whether this is of clinical importance has not been investigated.

Methods

Children with Plasmodium falciparum monoinfection and ≥20 parasites per 200 leucocytes at the Bandim Health Centre, Guinea-Bissau were randomized to receive paracetamol or placebo together with chloroquine for three days in a double blind randomized study. Temperature and symptoms were recorded twice daily during treatment and on day 3. The participants were interviewed and a malaria film taken once weekly until day 35. The data is in the form of grouped failure-times, the outcome of interest being time until parasitaemia during follow-up. Mantel-Haenszel weighted odds ratios are given. Other differences between and within the two groups have been tested using the Chi-square test and Mann-Whitney U test.

Results

In the evening of the day of inclusion, the temperature was slightly, but statistically insignificant, higher in the placebo group and significantly more children complained of headache. At no other time was a significant difference in temperature or symptoms detected. However, 6 children from the placebo-group as compared to two children from the paracetamol-group were admitted to hospital with high fever and convulsions by day 3. No differences in the cumulative percentages of children with adequate clinical and parasitological response were found in the intention-to-treat analysis or in the per-protocol analysis.

Conclusion

Fewer children had early treatment failure and the mean temperature was slightly lower in the afternoon on day 0 in the paracetamol group. However, the cumulative adequate clinical and parasitological cure rates were not significantly different during the period of study. It is doubtful whether adding paracetamol to the treatment of uncomplicated malaria in children is beneficial.

Trial registration

NCT00137566.

Background

Dementia is an incurable disease with devastating consequences for both patients and their relatives. The objective of this study is to describe the study protocol of a randomized controlled trial with assignment to either usual care or case-management by district nurses, among informal caregivers of older adults with dementia symptoms who live at home and the older adults who receive informal care.

Methods/design

In this randomized controlled trial, effectiveness as well as cost-effectiveness of case-management is evaluated. It concerns case-management in early-detected patients with dementia symptoms and their primary informal caregivers. Participants are followed up to twelve months after baseline assessment. The main outcome measure of the effect evaluation is the caregiver's sense of competence to care for the older person with dementia symptoms. The economic evaluation is performed from a societal perspective.

Discussion

This is one of the first trials on case-management that includes an economic evaluation. In addition, it concerns a tailor-made intervention in early-detected patients with dementia symptoms and their caregivers. The results of this randomized controlled trial will provide valuable information for health professionals and policy makers on effectiveness and cost-effectiveness of early tailor-made case-management for patients and their informal caregivers. Moreover, positive effects will challenge current health care systems to move to more pro-active approaches for this group.

Background

Pneumonia is a major risk factor of death after acute stroke. In a mouse model, preventive antibacterial therapy with moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly. In this study we investigate whether this approach is effective in stroke patients.

Methods

Preventive ANtibacterial THERapy in acute Ischemic Stroke (PANTHERIS) is a randomized, double-blind, placebo-controlled trial in 80 patients with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Patients received either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Primary endpoint was infection within 11 days. Secondary endpoints included neurological outcome, survival, development of stroke-induced immunodepression, and induction of bacterial resistance.

Findings

On intention-to treat analysis (79 patients), the infection rate at day 11 in the moxifloxacin treated group was 15.4% compared to 32.5% in the placebo treated group (p = 0.114). On per protocol analysis (n = 66), moxifloxacin significantly reduced infection rate from 41.9% to 17.1% (p = 0.032). Stroke associated infections were associated with a lower survival rate. In this study, neurological outcome and survival were not significantly influenced by treatment with moxifloxacin. Frequency of fluoroquinolone resistance in both treatment groups did not differ. On logistic regression analysis, treatment arm as well as the interaction between treatment arm and monocytic HLA-DR expression (a marker for immunodepression) at day 1 after stroke onset was independently and highly predictive for post-stroke infections.

Interpretation

PANTHERIS suggests that preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections.

Trial Registration

Controlled-Trials.com ISRCTN74386719

Background and aim

As non‐randomised studies have suggested that surgical decompression may reduce mortality in patients with space occupying hemispheric infarction, randomisation may be considered unethical in controlled trials testing this treatment strategy. We studied differences in recall of information and in appreciation of the informed consent procedure between representatives included in the Hemicraniectomy After Middle cerebral artery infarction with Life‐threatening Edema Trial (HAMLET) and representatives of patients participating in the randomised trial of Paracetamol (Acetaminophen) In Stroke (PAIS).

Methods

1 year after study inclusion, we contacted 30 consecutive representatives who had given informed consent for participation of their relative in HAMLET, and 30 for PAIS. Recall of trial details and appreciation of the informed consent procedure were investigated using standardised questionnaires and compared between the two groups.

Results

All 30 PAIS representatives and 28 HAMLET representatives were interviewed. Participation of their relative in a clinical trial was remembered by 86% of HAMLET and 40% of PAIS representatives (p<0.001). HAMLET representatives remembered more trial details (effect of the treatment under study (61% vs 3%, p<0.001); randomised treatment allocation (71% vs 0%, p<0.001)). With respect to appreciation of the informed consent procedure, we found no differences between the groups: in each trial, four representatives (14% vs 13%) had considered the question of randomisation unacceptable.

Conclusions

Participation of patients in a randomised controlled trial of surgical decompression for space occupying infarction is generally considered acceptable by their representatives, and recall of trial details is better than in a trial in which less vital issues are at stake.

Background: Paracetamol is a recommended symptomatic treatment of osteoarthritis (OA), but in clinical trials sample sizes have been relatively small and variable daily doses of paracetamol have been used.

Objectives: To determine the therapeutic efficacy of paracetamol in OA of the knee and identify predictive factors of clinical response to treatment.

Methods: A double blind, parallel group, placebo controlled trial of analgesic efficacy and safety of paracetamol versus placebo including 779 patients with OA of the knee. Patients were randomly assigned to receive paracetamol 4 g/day (n = 405) or placebo (n = 374) for 6 weeks. Symptomatic OA of the knee was required at inclusion with global pain intensity of the knee during physical activities for the past 24 hours of ⩾30 mm on a 100 mm visual analogue scale. The primary end point was a 30% decrease of global pain intensity of the knee. Intention to treat analyses were performed.

Results: The percentage of responders did not differ significantly between groups: 52.6% and 51.9% in paracetamol and placebo groups, respectively (p = 0.840). In a subgroup of patients with chronic mechanical knee pain without signs of inflammation (n = 123), the mean change in pain intensity from baseline was 25.2 mm v 15.2 mm, in the paracetamol (n = 63) and placebo (n = 60) groups, respectively—mean difference 10.0 mm; 95% CI 1.0 to 19.0; p = 0.0294. No serious adverse events were attributable to treatment.

Conclusion: A statistically significant symptomatic effect of oral paracetamol 4 g/day over placebo was not found, suggesting that paracetamol use in symptomatic OA of the knee should be further explored. The tolerability and safety of paracetamol, at the recommended maximum dose of 4 g/day, was confirmed over 6 weeks.

Background and Purpose

Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination.

Methods

The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke–funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 μg/kg bolus followed by 0.75 μg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy.

Results

Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA–only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate out-come of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group.

Conclusions

The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.

Background

Fever is common following infant vaccinations. Two randomized controlled trials demonstrated the efficacy of acetaminophen prophylaxis in preventing fever after whole cell pertussis vaccination, but acetaminophen prophylaxis has not been evaluated for prevention of fever following contemporary vaccines recommended for infants in the United States.

Methods

Children six weeks through nine months of age were randomized 1∶1 to receive up to five doses of acetaminophen (10–15 mg per kg) or placebo following routine vaccinations. The primary outcome was a rectal temperature ≥38°C within 32 hours following the vaccinations. Secondary outcomes included medical utilization, infant fussiness, and parents' time lost from work. Parents could request unblinding of the treatment assignment if the child developed fever or symptoms that would warrant supplementary acetaminophen treatment for children who had been receiving placebo.

Results

A temperature ≥38°C was recorded for 14% (25/176) of children randomized to acetaminophen compared with 22% (37/176) of those randomized to placebo but that difference was not statistically significant (relative risk [RR], 0.63; 95% CI, 0.40–1.01). Children randomized to acetaminophen were less likely to be reported as being much more fussy than usual (10% vs 24%) (RR, 0.42; 95% CI, 0.25–0.70) or to have the treatment assignment unblinded (3% vs 9%) (RR, 0.31; 95% CI, 0.11–0.83) than those randomized to placebo. In age-stratified analyses, among children ≥24 weeks of age, there was a significantly lower risk of temperature ≥38°C in the acetaminophen group (13% vs. 25%; p = 0.03).

Conclusion

The results of this relatively small trial suggest that acetaminophen may reduce the risk of post-vaccination fever and fussiness.

Trial registration

Clinicaltrials.gov NCT00325819

Background

Sex-related disparities in stroke have been previously reported. However, the influence of sex on the outcome of recurrent stroke in blacks is less clear. Our objective is to investigate the effect of sex on the outcome of recurrent non-fatal stroke in the African American Antiplatelet Stroke Prevention Study (AAASPS)

Methods

The AAASPS is a double-blind, randomized, controlled trial of recurrent stroke. Participants -967 black women and 842 black men- with non-cardioembolic ischemic stroke were assigned to receive ticlopidine or aspirin and followed for up to two years. The NIH Stroke Scale (NIHSS), modified Barthel score (mBS), and the Glasgow Outcome Scale (GOS) were determined at enrollment, at pre-specified 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 1,809 subjects enrolled in AAASPS, 186 subjects (89 women and 97 men) suffered recurrent non-fatal stroke. At enrollment, the NIHSS (2.87 for women and 3.00 for men; p=0.73), the mBS (18.26 for women and 18.52 for men; p=0.47) and the GOS (1.49 for women and 1.51 for men; p=0.86) were not significantly different. In follow-up and at the time of stroke recurrence, the NIHSS, mBS, and GOS 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=0.02). In the survival analysis, no significant difference in the time to recurrent stroke was found between women and men (p=0.69).

Conclusions

Although sex-related stroke disparities have been reported, in the AAASPS cohort outcomes for recurrent non-fatal non-cardioembolic 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.

Background

Adherence to non-specific prescription therapy may be associated with clinical outcomes beyond a given treatment effect. We assessed the association of blinded randomized pill prescription adherence with vascular outcomes after ischemic stroke.

Methods

We analyzed the Vitamin Intervention for Stroke Prevention (VISP) study database. VISP was a double-blind randomized trial, designed to determine whether high doses of vitamins (vs. low doses) would reduce recurrent stroke risk in 3,680 participants over a 2-year period. We examined the independent association of adherence with a composite endpoint (stroke, myocardial infarction, death).

Results

Among 3,357 (91%) subjects with complete data, women, non-White persons, current smokers, those not on statins and those without a history of coronary artery bypass surgery were significantly less likely to be optimally adherent. Over the trial, persons who adhered well to treatment were less likely to experience the combined outcome than those who adhered poorly (13.4 vs. 20.6%, p < 0.0001). After multivariable analysis using various adherence measures, there were no significant differences between ≥80% vs. <80% adherence, but compared to <65% adherence, pill adherence levels of ≥90 to <99% (HR 0.56, 95% CI = 0.34–0.91; p = 0.02) and ≥99% (HR 0.46, 95% CI = 0.29–0.73; p = 0.001) were associated with lower occurrence of the combined outcome at 18 months.

Conclusions

Long-term excellent adherence to non-specific pill prescription among ischemic stroke patients is independently associated with lower vascular risk, and is likely a marker of overall healthy behavior that may be helpful in targeting stroke patients with unhealthy practices.

Introduction:

A randomized double-blind trial (ECASS III) demonstrated that intravenous (IV) recombinant tissue plasminogen activator (rt-PA) administered between 3 and 4.5 hrs after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke. In May 2009, the American Stroke Association guidelines recommended the use of IV rt-PA for patients presenting within 3 and 4.5 hrs after symptom onset.

Objective:

To determine the rate of patients treated with IV rt-PA within the 3- and 4.5-hr time window and associated comparative outcomes in general practice.

Methods:

We retrospectively reviewed all patients who were treated with IV rt-PA at two comprehensive stroke centers from September 1, 2008 to July 31, 2010 and identified a total of 98 patients. In addition, we identified patients who arrived to the ED of those centers within 2.5 to 4 hrs of symptom onset between January 1, 2007 and June 30, 2010 and received only endovascular treatment. We compared the rates of favorable outcome (determined by using modified Rankin scale 0-2 at discharge and 3-month follow-up), and National Institutes of Health Stroke Scale (NIHSS) score improvement by ≥ 4 points or 0 at discharge among patients treated with IV rt-PA within 3-4.5 hrs with those who received IV rt-PA within 0-3 hrs, and subsequently with patients presenting at similar time window treated only with endovascular treatment.

Result:

Out of the total 98 IV rt-PA treated patients, 84 of them were treated within 0-3 hrs, and 14 within the 3--4.5 hrs. Twelve patients received endovascular treatment only for the specified time window. Mean admission NIHSS score ± standard deviation (SD) was 11.90 ± 6.72, 8.57 ± 5.40, and 11.75 ± 8.06, for the 0--3, 3--4.5 hrs, and endovascular only treatment groups, respectively. Favorable clinical outcome at discharge (50% vs. 56%, p=0.77), 3 months (64% vs. 64%, p=1.0), and NIHSS score improvement (43% vs. 58%, p=0.38) were not different between those treated within 3-4.5 and 0-3 hrs time windows. There appeared to be a non-significantly higher rate of favorable outcomes at discharge (25% vs. 50%, p=0.24), and at 3 months (42% vs. 64%, p=0.43) among patients treated with IV rt-PA within 3-4.5 hrs compared with those treated with primary endovascular treatment.

Conclusion:

An additional 14% of patients received IV rt-PA because of treatment window expansion from 3 to 4.5 hrs. Outcomes were comparable to those treated within 3 hrs of symptom onset. The shift of those patients from primary endovascular treatment does not appear to adversely affect patient outcomes.

OBJECTIVE: To evaluate the effects of acetaminophen on the incidence of adverse effects to, and the immunogenicity of, whole-virus influenza vaccine in health care workers. DESIGN: Prospective, randomized, double-blind placebo-controlled trial. SETTING: Health Sciences Centre, an acute care teaching hospital in Winnipeg. PARTICIPANTS: Of 474 hospital personnel who agreed to undergo influenza vaccination during the 1990-91 season 262 volunteered to participate in the study. INTERVENTIONS: A dose of 0.5 mL of inactivated trivalent whole-virus influenza vaccine was injected into the deltoid muscle. Volunteers were randomly assigned to ingest two capsules of acetaminophen in a half dose (162.5 mg per capsule) or a full dose (325 mg per capsule) or two identical placebo capsules. Capsules were to be taken at vaccination and at 4, 8 and 12 hours afterward. Subjects were asked to answer questions regarding six symptoms in a diary for the 3 days after vaccination and to record their ingestion of the study medication. MAIN OUTCOME MEASURES: Incidence of local (sore arm) and systemic (headache, fever, muscle ache, nausea and diarrhea) side effects as well as serum titres of hemagglutination inhibition (HAI) antibody to vaccine antigens before vaccination and 2 weeks and 6 months afterward. RESULTS: A total of 87, 87 and 88 subjects received the half dose, full dose and placebo respectively; 96% returned the diaries, 83% ingested all four doses of medication, and 87% volunteered all blood samples. Compared with the placebo group the incidence of sore arm was 25% to 28% lower in the half-dose and full-dose groups respectively at 24 hours after vaccination, and the rate of nausea was 90% lower in the full-dose group. The HAI titres were similar among the groups at the three test times. CONCLUSIONS: The full dose of acetaminophen significantly reduced the incidence of sore arm and nausea without affecting the antibody response. Acetaminophen use may increase the acceptance of influenza vaccine by health care workers in whom concern about side effects is an impediment to vaccination.