Heleen M. den Hertog

The Paracetamol (Acetaminophen) In Stroke (PAIS) trial: a multicentre, randomised, placebo-controlled, phase III trial

BACKGROUND High body temperature in the first 12-24 h after stroke onset is associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever. METHODS In a multicentre, randomised, double-blind, placebo-controlled trial, patients with ischaemic stroke or intracerebral haemorrhage and body temperature between 36 degrees C and 39 degrees C were randomly assigned treatment with paracetamol (6 g daily) or placebo within 12 h from symptom onset. Treatment allocation was based on a computer-generated list of random numbers with varying block size. The primary outcome was improvement beyond expectation on the modified Rankin scale at 3 months, according to the sliding dichotomy approach. This trial is registered, number ISRCTN74418480. FINDINGS Between March, 2003, and May, 2008, 1400 patients were randomly allocated treatment. 260 (37%) of 697 patients receiving paracetamol and 232 (33%) of 703 receiving placebo improved beyond expectation (adjusted odds ratio [OR] 1.20, 95% CI 0.96-1.50). In a post-hoc analysis of patients with baseline body temperature 37-39 degrees C, treatment with paracetamol was associated with improved outcome (1.43, 1.02-1.97). There were 55 serious adverse events in the paracetamol group (8%) and 70 in the placebo group (10%). INTERPRETATION These results do not support routine use of high-dose paracetamol in patients with acute stroke. Paracetamol might have a beneficial effect on functional outcome in patients admitted with a body temperature 37-39 degrees C, but this post-hoc finding needs further study. FUNDING Netherlands Heart Foundation.

Time to Reperfusion and Treatment Effect for Acute Ischemic Stroke: A Randomized Clinical Trial

IMPORTANCE Intra-arterial treatment (IAT) for acute ischemic stroke caused by intracranial arterial occlusion leads to improved functional outcome in patients treated within 6 hours after onset. The influence of treatment delay on treatment effect is not yet known. OBJECTIVE To evaluate the influence of time from stroke onset to the start of treatment and from stroke onset to reperfusion on the effect of IAT. DESIGN, SETTING, AND PARTICIPANTS The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) was a multicenter, randomized clinical open-label trial of IAT vs no IAT in 500 patients. The time to the start of treatment was defined as the time from onset of symptoms to groin puncture (TOG). The time from onset of treatment to reperfusion (TOR) was defined as the time to reopening the vessel occlusion or the end of the procedure in cases for which reperfusion was not achieved. Data were collected from December 3, 2010, to June 3, 2014, and analyzed (intention to treat) from July 1, 2014, to September 19, 2015. MAIN OUTCOMES AND MEASURES Main outcome was the modified Rankin Scale (mRS) score for functional outcome (range, 0 [no symptoms] to 6 [death]). Multiple ordinal logistic regression analysis estimated the effect of treatment and tested for the interaction of time to randomization, TOG, and TOR with treatment. The effect of treatment as a risk difference on reaching independence (mRS score, 0-2) was computed as a function of TOG and TOR. Calculations were adjusted for age, National Institutes of Health Stroke Scale score, previous stroke, atrial fibrillation, diabetes mellitus, and intracranial arterial terminus occlusion. RESULTS Among 500 patients (58% male; median age, 67 years), the median TOG was 260 (interquartile range [IQR], 210-311) minutes; median TOR, 340 (IQR, 274-395) minutes. An interaction between TOR and treatment (P = .04) existed, but not between TOG and treatment (P = .26). The adjusted risk difference (95% CI) was 25.9% (8.3%-44.4%) when reperfusion was reached at 3 hours, 18.8% (6.6%-32.6%) at 4 hours, and 6.7% (0.4%-14.5%) at 6 hours. CONCLUSION AND RELEVANCE For every hour of reperfusion delay, the initially large benefit of IAT decreases; the absolute risk difference for a good outcome is reduced by 6% per hour of delay. Patients with acute ischemic stroke require immediate diagnostic workup and IAT in case of intracranial arterial vessel occlusion. TRIAL REGISTRATION trialregister.nl Identifier: NTR1804.

Collateral Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in Patients with Proximal Anterior Circulation Stroke

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals (P=0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com. Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

Therapeutic hypothermia in acute ischemic stroke

Increased body temperatures are common in the acute phase of stroke. Experimental and clinical studies have suggested that increased body temperatures are related to poor outcome. In animal studies of focal cerebral ischemia, early hypothermia consistently reduced infarct volume. Based on these findings, several Phase II clinical trials have been performed to study physical methods to reduce body temperature in patients with acute stroke. The feasibility and safety of these methods have not yet been established with sufficient certainty. Pharmacological lowering of body temperature may be an attractive alternative approach. In guidelines for the treatment of acute stroke, antipyretics are generally recommended to reduce fever, although their effect on functional outcome is unknown. There is currently no evidence from randomized trials to support routine use of physical or pharmacological cooling in acute stroke. Large randomized clinical trials are needed to study the effect of both physical and medical cooling on functional outcome after stroke.

PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480]

BackgroundIn patients with acute stroke, increased body temperature is associated with large lesion volumes, high case fatality, and poor functional outcome. A 1°C increase in body temperature may double the odds of poor outcome. Two randomized double-blind clinical trials in patients with acute ischemic stroke have shown that treatment with a daily dose of 6 g acetaminophen (paracetamol) results in a small but rapid and potentially worthwhile reduction of 0.3°C (95% CI: 0.1–0.5) in body temperature. We set out to test the hypothesis that early antipyretic therapy reduces the risk of death or dependency in patients with acute stroke, even if they are normothermic.Methods/designParacetamol (Acetaminophen) In Stroke (PAIS) is a randomized, double-blind clinical trial, comparing high-dose acetaminophen with placebo in 2500 patients. Inclusion criteria are a clinical diagnosis of hemorrhagic or ischemic stroke and the possibility to start treatment within 12 hours from onset of symptoms. The study will have a power of 86% to detect an absolute difference of 6% in the risk of death or dependency at three months, and a power of 72% to detect an absolute difference of 5%, at a 5% significance level.DiscussionThis is a simple trial, with a drug that only has a small effect on body temperature in normothermic patients. However, when lowering body temperature with acetaminophen does have the expected effectiveness, 20 patients will have to be treated to prevent dependency or death in one.

Prevalence of Prediabetes and Newly Diagnosed Diabetes in Patients with a Transient Ischemic Attack or Stroke

Background: Patients with a transient ischemic attack (TIA) or stroke and prediabetes or newly diagnosed diabetes are at high risk of recurrent stroke or cardiovascular events. This underlines the importance of accurate screening for impaired glucose metabolism in clinical practice. Fasting plasma glucose levels are currently the most commonly measured glycemic parameter to detect prediabetes or diabetes, even if 2-hour postload glucose and glycosylated hemoglobin levels can be used as well. We assessed the prevalence of prediabetes and newly diagnosed diabetes with different screening methods, including fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in consecutive patients with recent TIA, ischemic stroke or intracerebral hemorrhage admitted to the stroke unit or visiting the specialized TIA outpatient clinic in the Erasmus Medical Center, Rotterdam, The Netherlands. Methods: We measured fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels in 269 patients with a TIA, 374 with ischemic stroke and 57 with intracerebral hemorrhage, all without a history of diabetes mellitus. Prediabetes was defined as fasting plasma glucose levels of 5.6-6.9 mmol/l and/or 2-hour postload glucose levels of 7.8-11.0 mmol/l and/or glycosylated hemoglobin levels of 5.7-6.4%. Newly diagnosed diabetes was defined as fasting plasma glucose levels of ≥7.0 mmol/l and/or 2-hour postload levels of ≥11.1 mmol/l and/or glycosylated hemoglobin levels of ≥6.5%. The diagnosis was based on a one-time measurement. Results: Based on fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels combined, 365 patients (52%) were identified as prediabetics and 188 (27%) as having newly diagnosed diabetes. Patients with intracerebral hemorrhage had more often newly diagnosed diabetes compared with patients with an ischemic stroke or a TIA [27 (47%) and 161 (25%), respectively; p < 0.001]; the prevalence of prediabetes was similar. Newly diagnosed diabetes was identified more frequently by 2-hour postload glucose levels (n = 162; 23%) than by fasting plasma glucose (n = 49; 7%) or glycosylated hemoglobin levels (n = 36; 5%). About one third of the patients with normal fasting glucose levels has impaired glucose tolerance or elevated glycosylated hemoglobin levels. Conclusions: Prediabetes and newly diagnosed diabetes are highly prevalent in patients with a TIA or stroke. The majority of these patients would not have been identified by fasting plasma glucose levels alone. Both 2-hour postload glucose and glycosylated hemoglobin levels identify more patients with a disturbed glucose metabolism.

Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): Protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36·5°C or above

Rationale In the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 37·0°C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1·43; 95% confidence interval: 1·02–1·97). This relation was also found in the patients with a body temperature of 36·5°C or higher (odds ratio 1·31; 95% confidence interval 1·01–1·68). These findings need confirmation. Aim The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36·5°C or above on functional outcome. Design The Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 0·05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36·5°C or above will be included within 12 h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. Study outcomes The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. Discussion If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.

Prediabetes in Patients with Stroke or Transient Ischemic Attack: Prevalence, Risk and Clinical Management

Background: The prevalence of diabetes is emerging worldwide and is an important modifiable risk factor for stroke. People with prediabetes, an intermediate metabolic state between normal glucose metabolism and diabetes, have a tenfold increased risk of developing diabetes compared to those with a normal glucose metabolism. Prediabetes is comprised of impaired fasting glucose and/or impaired glucose tolerance and/or disturbed glycosylated hemoglobin levels. Prediabetes is highly prevalent in nondiabetic patients with transient ischemic attack (TIA) or ischemic stroke and nearly doubles their risk of stroke. This offers new options for secondary stroke prevention. Summary: Several detection methods exist for identifying (pre)diabetes, including fasting plasma glucose, 2-hour postload glucose and glycosylated hemoglobin levels. The concordance between these tests is not 100%, and they seem to be complementary. Screening for (pre)diabetes after stroke with fasting plasma glucose levels alone is insufficient, and 2-hour postload glucose and/or glycosylated hemoglobin levels should be determined as well. The prevalence of prediabetes in previously nondiabetic patients with a recent TIA or stroke ranges from 23 to 53%. This high prevalence in the acute phase after stroke can be transient or persistent, representing undiagnosed abnormal glucose metabolism. Impaired fasting glucose and impaired glucose tolerance have different pathophysiological mechanisms, including hepatic insulin resistance and muscle insulin resistance, respectively. Prediabetes seems to be a modest predictor for stroke, but doubles the risk for recurrent stroke. The relation between prediabetes after stroke and functional outcome is still unknown. However, it is most likely that prediabetes is a risk factor for a poor clinical outcome after stroke. There is a growing recognition that patients with prediabetes should be treated more aggressively. Both lifestyle and pharmacological interventions are possible treatment strategies. They are at least equally effective in preventing progression to diabetes. Lifestyle changes are difficult to maintain over a long period. The evidence of pharmacological interventions on stroke or other cardiovascular diseases is limited though and is still subject of several clinical trials. Conclusions: As the prevalence of prediabetes is growing rapidly, prediabetes might become one of the most important modifiable therapeutic targets in both primary and secondary prevention.

Increased Benefit of Alteplase in Patients with Ischemic Stroke and a High Body Temperature

Background: In observational studies, a high body temperature has been associated with unfavorable outcome. In in vitro studies, the fibrinolytic activity of alteplase decreased 5% per degree Celsius reduction in temperature. The modifying effect of body temperature on treatment with alteplase in patients with acute ischemic stroke is unclear. We assessed the influence of baseline body temperature on the effect of alteplase on functional outcome in patients with acute ischemic stroke, included in the Paracetamol (Acetaminophen) in Stroke (PAIS) trial. Methods: PAIS was a randomized, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke. For this study, we selected all patients with ischemic stroke and randomization within 6 h of symptom onset. We estimated the effect of treatment with alteplase on the modified Rankin Scale score at 3 months with ordinal logistic regression, stratified by baseline body temperature. We made adjustments for confounding factors and expressed associations as adjusted odds ratios (aOR) with 95% confidence intervals (CI). We also tested for interaction between treatment with alteplase and body temperature. Results: We included 647 of the 1,400 patients in PAIS in our study. Treatment with alteplase was associated with improved functional outcome at 3 months (aOR 1.51, 95% CI 1.09–2.08). In the 286 patients (44%) with a baseline body temperature of 37.0°C or higher, alteplase was associated with a larger effect (aOR 2.13, 95% CI 1.28–3.45) than in patients with a temperature below 37.0°C (aOR 1.11, 95% CI 0.71–1.69). A test for interaction between body temperature and alteplase did not reach statistical significance (p = 0.18). Conclusion: Patients with ischemic stroke and a high body temperature may have a larger benefit of treatment with alteplase than patients with lower body temperatures. These findings are in line with those from in vitro studies, in which lowering temperature decreased the fibrinolytic activity of the enzyme alteplase. This interaction should be explored further in randomized clinical trials of thrombolytic therapy or modification of body temperature. Trials of therapeutic hypothermia should be controlled for treatment with thrombolytics, and trials of thrombolytic treatment should consider body temperature as a potential effect modifier.

Newly-Diagnosed Disturbed Glucose Metabolism is Associated withAtherosclerosis in Patients with Transient Ischemic Attack or IschemicStroke

Objective: Newly-diagnosed disturbed glucose metabolism is highly prevalent in non-diabetic patients with transient ischemic attack (TIA) or ischemic stroke, and increases the risk of recurrent stroke. Diabetes mellitus is associated with atherosclerosis. We aimed to assess whether newly-diagnosed disturbed glucose metabolism is associated with atherosclerosis as well. Research design and methods: Patients with a recent TIA or ischemic stroke were classified in three groups based on glucose levels and use of antidiabetic drugs. Pre-existent diabetes mellitus was defined as the use of antidiabetic drugs prior to the event. Newly-diagnosed disturbed glucose metabolism was defined as two or more disturbed glucose tests: fasting plasma glucose level ≥ 5.6 mmol/L, 2-hour post-load glucose level ≥ 7.8 mmol/L, and/or glycosylated hemoglobin level ≥ 39 mmol/mol. We used CT-angiography to assess stenosis in the carotid artery bifurcations and calcification volume in the aortic arch, carotid bifurcations and intracranial carotid arteries. The relation between glucose groups and measures of atherosclerosis was expressed as odds ratios and beta coefficients with corresponding 95% CI, adjusted for potential confounders. Results: Of the 1217 patients, 384 (32%) had newly-diagnosed disturbed glucose metabolism, and 210 (17%) had pre-existent diabetes mellitus. Newly-diagnosed disturbed glucose metabolism was independently associated with stenosis ≥ 50% (aOR (95%CI) 1.15 (1.04-2.20)). Pre-existent diabetes mellitus was associated with stenosis ≥ 50% and with calcification volume in all regions, especially in patients without the use of cholesterol-lowering drugs prior to the event. Conclusions: Our study shows that newly-diagnosed disturbed glucose metabolism in patients with a recent TIA or ischemic stroke is associated with more severe extra- and intracranial atherosclerosis, similar to pre-existent diabetes mellitus.