RESUMEN
BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
Asunto(s)
Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Hematoma , Proteínas Recombinantes , Humanos , Inhibidores del Factor Xa/efectos adversos , Inhibidores del Factor Xa/uso terapéutico , Anciano , Masculino , Femenino , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/inducido químicamente , Persona de Mediana Edad , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Factor Xa/uso terapéutico , Factor Xa/efectos adversos , Hematoma/inducido químicamente , Hematoma/tratamiento farmacológico , Anciano de 80 o más Años , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/complicaciones , Enfermedad AgudaRESUMEN
BACKGROUND: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied. METHODS: We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding. RESULTS: A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001). CONCLUSIONS: Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).
Asunto(s)
Aspirina/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Ticagrelor/uso terapéutico , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Evaluación de la Discapacidad , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemorragia/inducido químicamente , Humanos , Ataque Isquémico Transitorio/complicaciones , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Prevención Secundaria , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/prevención & control , Ticagrelor/efectos adversosRESUMEN
Background and Purpose: In patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit. Methods: In a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points. Results: In 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups. Conclusions: In patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.
Asunto(s)
Aspirina/administración & dosificación , Hemorragia Cerebral/inducido químicamente , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ticagrelor/administración & dosificación , Adulto , Anciano , Hemorragia Cerebral/epidemiología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Ataque Isquémico Transitorio/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. METHODS: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo added to aspirin (300-325 mg on day 1 followed by 75-100 mg daily for days 2-30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. RESULTS: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56-0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19-171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74-1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04-16.9], P=0.001). CONCLUSIONS: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19-171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.
Asunto(s)
Aspirina/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Trastornos Cerebrovasculares/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ticagrelor/uso terapéutico , Anciano , Aterosclerosis/complicaciones , Trastornos Cerebrovasculares/complicaciones , Constricción Patológica , Terapia Antiplaquetaria Doble , Femenino , Humanos , Ataque Isquémico Transitorio/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Prevención Secundaria , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND/AIMS: Standard approaches to trial design and analyses can be inefficient and non-pragmatic. Failure to consider a range of outcomes impedes evidence-based interpretation and reduces power. Traditional approaches synthesizing information obtained from separate analysis of each outcome fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. Pragmatic and efficient approaches to trial design and analyses are needed. METHODS: Approaches providing a pragmatic assessment of benefits and harms of interventions, summarizing outcomes experienced by patients, and providing sample size efficiencies are described. Ordinal outcomes recognize finer gradations of patient responses. Desirability of outcome ranking is an ordinal outcome combining benefits and harms within patients. Analysis of desirability of outcome ranking can be based on rank-based methodologies including the desirability of outcome ranking probability, the win ratio, and the proportion in favor of treatment. Partial credit analyses, involving grading the levels of the desirability of outcome ranking outcome similar to an academic test, provides an alternative approach. The methodologies are demonstrated using the acute stroke or transient ischemic attack treated with aspirin or ticagrelor and patient outcomes study (SOCRATES; NCT01994720), a randomized clinical trial. RESULTS: Two 5-level ordinal outcomes were developed for SOCRATES. The first was based on a modified Rankin scale. The odds ratio is 0.86 (95% confidence interval = 0.75, 0.99; p = 0.04) indicating that the odds of worse stroke categorization for a trial participant assigned to ticagrelor is 0.86 times that of a trial participant assigned to aspirin. The 5-level desirability of outcome ranking outcome incorporated and prioritized survival; the number of strokes, myocardial infarction, and major bleeding events; and whether a stroke event was disabling. The desirability of outcome ranking probability and win ratio are 0.504 (95% confidence interval = 0.499, 0.508; p = 0.10) and 1.11 (95% confidence interval = 0.98, 1.26; p = 0.10), respectively, implying that the probability of a more desirable result with ticagrelor is 50.4% and that a more desirable result occurs 1.11 times more frequently on ticagrelor versus aspirin. CONCLUSION: Ordinal outcomes can improve efficiency through required pre-specification, careful construction, and analyses. Greater pragmatism can be obtained by composing outcomes within patients. Desirability of outcome ranking provides a global assessment of the benefits and harms that more closely reflect the experience of patients. The desirability of outcome ranking probability, the proportion in favor of treatment, the win ratio, and partial credit can more optimally inform patient treatment, enhance the understanding of the totality of intervention effects on patients, and potentially provide efficiencies over standard analyses. The methods provide the infrastructure for incorporating patient values and estimating personalized effects.
Asunto(s)
Aspirina/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Accidente Cerebrovascular/tratamiento farmacológico , Ticagrelor/uso terapéutico , Adulto , Humanos , Oportunidad Relativa , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ensayos Clínicos Pragmáticos como Asunto/métodos , Proyectos de Investigación , Resultado del TratamientoRESUMEN
Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD. Methods- We randomized 13 199 patients with noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to 90-day ticagrelor or aspirin treatment within 24 hours of symptom onset. For this analysis, 13 126 patients were categorized by TLD as <12 hours or ≥12 hours from start of index event. The primary end point was the composite of stroke, myocardial infarction, or death within 90 days. Major bleeding was the primary safety end point. Results- TLD was <12 hours in 4403 (33.5%) and ≥12 hours in 8723 (66.5%). The Kaplan-Meier% for the primary end point for all patients with TLD<12 hours was 7.5% versus 6.9% in TLD≥12 hours. Among patients with TLD<12 hours, the primary end point occurred in 147/2196 (6.8%) randomized to ticagrelor and in 184/2207 (8.3%) randomized to aspirin (hazard ratio, 0.79; 95% CI, 0.64-0.98; P=0.036). Among patients with TLD≥12 hours, the primary end point occurred in 6.7% patients randomized to ticagrelor versus 7.0% to aspirin (hazard ratio, 0.95; 95% CI, 0.81-1.12; P=0.55). There was no significant treatment-by-TLD interaction. Major bleeding rates were comparable on ticagrelor and aspirin, regardless of TLD. Conclusions- The event rate for the primary end point was higher in patients treated early (<12 hours) versus later (≥12 hours). In this exploratory analysis, a larger numerical difference in the primary end point was observed among patients on ticagrelor than on aspirin when TLD was <12 hours compared with ≥12 hours, although the interaction terms for treatment-by-TLD were not significant. For major bleeding, no relation to TLD was observed. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01994720.
Asunto(s)
Aspirina/administración & dosificación , Aspirina/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Ticagrelor/administración & dosificación , Ticagrelor/uso terapéutico , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Determinación de Punto Final , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Inhibidores de Agregación Plaquetaria/efectos adversos , Recurrencia , Riesgo , Ticagrelor/efectos adversos , Tiempo de TratamientoRESUMEN
BACKGROUND AND PURPOSE: SOCRATES (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), comparing ticagrelor with aspirin in patients with acute cerebral ischemia, found a nonsignificant 11% relative risk reduction for stroke, myocardial infarction, or death (P=0.07). Aspirin intake before randomization could enhance the effect of ticagrelor by conferring dual antiplatelet effect during a high-risk period for subsequent stroke. Therefore, we explored the efficacy and safety of ticagrelor versus aspirin in the patients who received any aspirin the week before randomization. METHODS: A prespecified subgroup analysis in SOCRATES (n=13 199), randomizing patients with acute ischemic stroke (National Institutes of Health Stroke Scale score of ≤5) or transient ischemic attack (ABCD2 score of ≥4) to 90-day treatment with ticagrelor or aspirin. Patients in the prior-aspirin group had received any aspirin within the week before randomization. Primary end point was time to stroke, myocardial infarction, or death. Safety end point was PLATO (Study of Platelet Inhibition and Patient Outcomes) major bleeding. RESULTS: The 4232 patients in the prior-aspirin group were older, had more vascular risk factors, and vascular disease than the other patients. In the prior-aspirin group, the primary end point occurred in 138/2130 (6.5%) of patients on ticagrelor and in 177/2102 (8.3%) on aspirin (hazard ratio, 0.76; 95% confidence interval, 0.61-0.95; P=0.02); in patients with no prior-aspirin usage an event occurred in 304/4459 (6.9%) and 320/4508 (7.1%) on ticagrelor and aspirin, respectively (hazard ratio, 0.96; 95% confidence interval, 0.82-1.12; P=0.59). The treatment-by-prior-aspirin interaction was not statistically significant (P=0.10). In the prior-aspirin group, major bleeding occurred in 0.7% and 0.4% of patients on ticagrelor and aspirin, respectively (hazard ratio, 1.58; 95% confidence interval, 0.68-3.65; P=0.28). CONCLUSIONS: In this secondary analysis from SOCRATES, fewer primary end points occurred on ticagrelor treatment than on aspirin in patients receiving aspirin before randomization, but there was no significant treatment-by-prior-aspirin interaction. A new study will investigate the benefit-risk of combining ticagrelor and aspirin in patients with acute cerebral ischemia (URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429). CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.
Asunto(s)
Aspirina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Hemorragia/inducido químicamente , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Ticagrelor/uso terapéutico , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/inducido químicamente , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticagrelor/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Ticagrelor is an effective antiplatelet therapy among patients with atherosclerotic disease and, therefore, could be more effective than aspirin in preventing recurrent stroke and cardiovascular events among patients with embolic stroke of unknown source (ESUS), which includes patients with ipsilateral stenosis <50% and aortic arch atherosclerosis. METHODS: We randomized 13 199 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2-90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2-90) within 24 hours of symptom onset. In all patients, investigators informed on the presence of ipsilateral stenosis ≥50%, small deep infarct <15 mm, and on cardiac source of embolism detected after enrollment or rare causes, which allowed to construct an ESUS category in all other patients with documented brain infarction. The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. RESULTS: ESUS was identified in 4329 (32.8%) patients. There was no treatment-by-ESUS category interaction (P=0.83). Hazard ratio in ESUS patients was 0.87 (95% confidence interval, 0.68-1.10; P=0.24). However, hazard ratio was 0.51 (95% confidence interval, 0.29-0.90; P=0.02) in ESUS patients with ipsilateral stenosis <50% or aortic arch atherosclerosis (n=961) and 0.98 (95% confidence interval, 0.76-1.27; P=0.89) in the remaining ESUS patients (n=3368; P for heterogeneity =0.04). CONCLUSIONS: In this post hoc, exploratory analysis, we found no treatment-by-ESUS category interaction. ESUS subgroups have heterogeneous response to treatment (Funded by AstraZeneca). CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.
Asunto(s)
Adenosina/análogos & derivados , Aspirina/uso terapéutico , Embolia Intracraneal/tratamiento farmacológico , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Adenosina/uso terapéutico , Anciano , Enfermedades de la Aorta/epidemiología , Aterosclerosis/epidemiología , Estenosis Carotídea/epidemiología , Femenino , Humanos , Embolia Intracraneal/epidemiología , Masculino , Persona de Mediana Edad , Mortalidad , Infarto del Miocardio/epidemiología , Recurrencia , Accidente Cerebrovascular/epidemiología , Ticagrelor , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: The ANNEXA-4 trial measured hemostatic efficacy of andexanet alfa in patients with major bleeding taking factor Xa inhibitors. A proportion of this was traumatic and nontraumatic intracranial bleeding. Different measurements were applied in the trial including volumetrics to assess for intracranial bleeding depending on the compartment involved. We aimed to determine the most reliable way to measure intracranial hemorrhage (ICrH) volume by comparing individual brain compartment and total ICrH volume. METHODS: Thirty patients were randomly selected from the ANNEXA-4 database to assess measurement of ICrH volume by compartment and in total. Total and compartmental hemorrhage volumes were measured by five readers using Quantomo software. Each reader measured baseline hemorrhage volumes twice separated by 1 week. Twenty-eight different ANNEXA-4 subjects were also randomly selected to assess intra-rater reliability of total ICrH volume measurement change at baseline and 12-h follow up, performed by three readers twice to assess hemostatic efficacy categories used in ANNEXA-4. RESULTS: Compartmental minimal detectable change percentages (MDC%) ranged between 9.72 and 224.13, with the greatest measurement error occurring in patients with a subdural hemorrhage. Total ICrH volume measurements had the lowest MDC%, which ranged between 6.57 and 33.52 depending on the reader. CONCLUSION: Measurement of total ICrH volumes is more accurate than volume by compartment with less measurement error. Determination of hemostatic efficacy was consistent across readers, and within the same reader, as well as when compared to consensus read. Volumetric analysis of intracranial hemostatic efficacy is feasible and reliable when using total ICrH volumes.
Asunto(s)
Factor Xa , Hemorragias Intracraneales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/uso terapéutico , Anciano , Reproducibilidad de los Resultados , Adulto , Encéfalo/diagnóstico por imagenRESUMEN
Objective: THALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed. Methods: Cost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective. Results: One-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of 95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (-1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions. Conclusion: One month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA. Trial registration number: NCT03354429.
RESUMEN
BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the short-term time-course benefit and risk of ticagrelor with aspirin in acute mild-moderate ischemic stroke or high-risk TIA in The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial. METHODS: In an exploratory analysis of the THALES trial, we evaluated the cumulative incidence of irreversible efficacy and safety outcomes at different time points during the 30-day treatment period. The efficacy outcome was major ischemic events defined as a composite of ischemic stroke or nonhemorrhagic death. The safety outcome was major hemorrhage defined as a composite of intracranial hemorrhage and fatal bleedings. Net clinical impact was defined as the combination of these 2 endpoints. RESULTS: This analysis included a total of 11,016 patients (5,523 in the ticagrelor-aspirin group, 5,493 in the aspirin group) with a mean age of 65 years, and 39% were women. The reduction of major ischemic events by ticagrelor occurred in the first week (4.1% vs 5.3%; absolute risk reduction 1.15%, 95% CI 0.36%-1.94%) and remained throughout the 30-day treatment period. An increase in major hemorrhage was seen during the first week and remained relatively constant in the following weeks (absolute risk increase ≈0.3%). Cumulative analysis showed that the net clinical impact favored ticagrelor-aspirin in the first week (absolute risk reduction 0.97%, 95% CI, 0.17%-1.77%) and remained constant throughout the 30 days. DISCUSSION: In patients with mild-moderate ischemic stroke or high-risk TIA, the treatment effect of ticagrelor-aspirin was present from the first week. The ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the treatment period, which may support the use of 30-day treatment with ticagrelor and aspirin in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients with mild-moderate ischemic stroke or high-risk TIA, the ischemic benefit of ticagrelor-aspirin outweighs the risk of major hemorrhage throughout the 30-day treatment period.
Asunto(s)
Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Anciano , Aspirina/uso terapéutico , Quimioterapia Combinada , Femenino , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Isquemia , Ataque Isquémico Transitorio/inducido químicamente , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/epidemiología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/epidemiología , Masculino , Inhibidores de Agregación Plaquetaria/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Ticagrelor/uso terapéuticoRESUMEN
INTRODUCTION: Data on the prognostic value of hypertensive response to exercise in cardiovascular disease are limited. The aim was to determine whether SBP reactions during exercise have any prognostic value in relation to the long-term risk of stroke and myocardial infarction (MI). PATIENTS AND METHODS: A representative cohort of men from Gothenburg, Sweden, born in 1913, who performed a maximum exercise test at age 54 years, (nâ=â604), was followed-up for a maximum of 44 years with regard to stroke and MI. RESULTS: Among the 604 men, the mean resting and maximum SBP was 141.5 (SD 18.8) and 212.1 (SD 24.6)âmmHg, respectively. For maximum SBP, the risk of stroke increased by 34% (hazard ratio 1.34, 95% confidence interval 1.11-1.61) per 1-SD increase, while no risk increase was observed for MI. The highest risk of stroke among blood pressure groups was observed among men with a resting SBP of at least 140âmmHg and a maximum SBP of at least 210âmmHg with an hazard ratio of 2.09 (95% confidence interval 1.29-3.40), compared with men with a resting SBP of less than 140âmmHg and a maximum SBP of less than 210âmmHg, independent of smoking, blood glucose, cholesterol and BMI. CONCLUSION: Among middle-aged men with high resting and maximum blood pressure during maximum exercise workload, an increased risk of stroke was observed but not for MI. Further studies with larger sample sizes are needed to investigate the underlying mechanisms of the increased risk of stroke among individuals with hypertensive response to exercise.
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Hipertensión , Infarto del Miocardio , Accidente Cerebrovascular , Anciano de 80 o más Años , Presión Sanguínea , Estudios de Seguimiento , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiologíaRESUMEN
INTRODUCTION: Recent trials report positive results for preventing vascular events with dual antiplatelet therapy (DAPT) in patients with high-risk TIA or minor ischemic stroke. We aimed to investigate this population regarding influence of age on vascular risk factors, hospital stay and mortality. PATIENTS AND METHODS: Data on patients aged 40-100 years with TIA or ischemic stroke in the Swedish Stroke Register during 2012-13 were linked with national registers. To identify patients with high-risk TIA (ABCD2 ≥6) or minor ischemic stroke (NIHSS ≤5) eligible for DAPT, we excluded patients with atrial fibrillation, anticoagulant use, prior major bleeding, or unknown stroke severity. FINDINGS: We identified 10,053 potential DAPT-candidates (mean age 72.6 years, 45.2% female, 16.4% with TIA). With advancing age, most vascular risk factors increased. Antiplatelet treatment increased from 31.9% before the event to 95.5% after discharge. Within 1 year following index event, the proportion of patients with ≥1 re-admission increased with age (29.2% in 40-64 year-olds; 47.2% in 85-100 year-olds). All-cause death per 100 person-years was 6.9 (95% CI 6.4-7.4) within 1 year, and highest in the first 30 days (15.2; 95% CI 12.8-18.2). For each year of increased age, the risk of death increased with 3.5% (p = 0.128) in patients 40-64 years and with 11.8% (p < 0.001) in those ≥85 years. CONCLUSIONS: While in theory representing a subset of patients with mild injury, our observational study highlights substantial use of health-care resources and high mortality rates among patients with high-risk TIA or minor ischemic stroke assumed eligible for DAPT.
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Importance: Prior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup. Objective: To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5). Design, Setting, and Participants: The THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021. Interventions: Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after symptom onset. All patients received aspirin, 300 to 325 mg, on day 1 followed by aspirin, 75 to 100 mg, daily on days 2 to 30. Patients were observed for 30 additional days. Main Outcomes and Measures: The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding. Results: In total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke group, 1293 (39.0%) were female, and the mean (SD) age was 64.5 (10.8) years; of those in the less severe stroke group, 2518 (37.7%) were female, and the mean (SD) age was 64.8 (11.2) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129 of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and 5.7% (190 of 3312) for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66-1.01) (P for interaction = .88). Severe bleeding occurred in 8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16 patients (0.5%) and 3 patients (0.1%), respectively, with less severe stroke (P for interaction = .26). Conclusions and Relevance: In this study, patients with a moderate ischemic stroke had consistent benefit from ticagrelor plus aspirin vs aspirin alone compared with patients with less severe ischemic stroke, with no further increase in the risk of intracranial bleeding or other severe bleeding events. Trial Registration: ClinicalTrials.gov Identifier: NCT03354429.
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Aspirina/administración & dosificación , Terapia Antiplaquetaria Doble/métodos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Ticagrelor/administración & dosificación , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Resultado del TratamientoRESUMEN
IMPORTANCE: Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke. OBJECTIVE: To evaluate the superiority of ticagrelor added to aspirin in preventing disabling stroke and to understand the factors associated with recurrent disabling stroke. DESIGN, SETTING, AND PARTICIPANTS: The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) was a randomized clinical trial conducted between January 22, 2018, and December 13, 2019, with a 30-day follow-up, at 414 hospitals in 28 countries. The trial included 11â¯016 patients with a noncardioembolic, nonsevere ischemic stroke or high-risk TIA, including 10â¯803 with modified Rankin Scale score (mRS) recorded at 30 days. INTERVENTIONS: Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily for days 2-30) or placebo within 24 hours of symptom onset. All patients received aspirin, 300 to 325 mg on day 1 followed by 75 to 100 mg daily for days 2 to 30. MAIN OUTCOMES AND MEASURES: Time to the occurrence of disabling stroke (progression of index event or new stroke) or death within 30 days, as measured by mRS at day 30. Disabling stroke was defined by mRS greater than 1. RESULTS: Among participants with 30-day mRS greater than 1, mean age was 68.1 years, 1098 were female (42.6%), and 2670 had an ischemic stroke (95.8%) as a qualifying event. Among 11â¯016 patients, a primary end point with mRS greater than 1 at 30 days occurred in 221 of 5511 patients (4.0%) randomized to ticagrelor and in 260 of 5478 patients (4.7%) randomized to placebo (hazard ratio [HR], 0.83; 95% CI, 0.69-0.99, P = .04). A primary end point with mRS 0 or 1 at 30 days occurred in 70 of 5511 patients (1.3%) and 87 of 5478 patients (1.6%) (HR, 0.79; 95% CI, 0.57-1.08; P = .14). The ordinal analysis of mRS in patients with recurrent stroke showed a shift of the disability burden following a recurrent ischemic stroke in favor of ticagrelor (odds ratio, 0.77; 95% CI, 0.65-0.91; P = .002). Factors associated with disability were baseline National Institutes of Health Stroke Scale score 4 to 5, ipsilateral stenosis of at least 30%, Asian race/ethnicity, older age, and higher systolic blood pressure, while treatment with ticagrelor was associated with less disability. CONCLUSIONS AND RELEVANCE: In patients with TIA and minor ischemic stroke, ticagrelor added to aspirin was superior to aspirin alone in preventing disabling stroke or death at 30 days and reduced the total burden of disability owing to ischemic stroke recurrence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03354429.
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BACKGROUND AND PURPOSE: C-reactive protein (CRP) is a determinant of stroke, but there are no prospective studies on CRP and first ischemic stroke divided into etiologic subtypes. Our primary aim was to study CRP as a determinant of ischemic stroke, classified according to Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria, and intracerebral hemorrhage (ICH) in a prospective study. A secondary aim was to study the relationship between the 1444C>T polymorphism, plasma levels of CRP and stroke. METHODS: The study was a prospective population-based case-referent study nested within the Northern Sweden Cohorts. We defined 308 cases of ischemic stroke and 61 ICH. Two controls for each case were defined from the same cohort. RESULTS: The OR for the highest (>3 mg/l) versus lowest group (<1 mg/l) of CRP was 2.58 (95% CI 1.74-3.84) for ischemic stroke and 1.63 (95% CI 0.67-3.93) for ICH. In a multivariate model including traditional risk factors, CRP remained associated with ischemic stroke (OR 2.06; 95% CI 1.29-3.29). Small-vessel disease was associated with CRP in the multivariate model (OR 3.88; 95% CI 1.10-13.7). The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP but neither with ischemic stroke nor with ICH. CONCLUSIONS: This prospective population-based study shows that CRP is significantly associated with the risk of having a first ischemic stroke, especially for small-vessel disease. No significant associations were found between the CRP 1444C>T polymorphism and any stroke subtype.
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Proteína C-Reactiva/metabolismo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/epidemiología , Proteína C-Reactiva/genética , Estudios de Casos y Controles , Hemorragia Cerebral/sangre , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/etnología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo Genético/genética , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/etnología , SueciaRESUMEN
OBJECTIVE: To examine factors associated with disability following TIA and minor stroke, including poststroke complications such as stroke recurrence, major bleeding, and other adverse medical events. METHODS: The SOCRATES trial randomized patients with TIA/minor stroke (NIH Stroke Scale [NIHSS] score ≤5) within 24 hours of onset. We performed a post hoc analysis of factors associated with disability (modified Rankin Scale [mRS] score >1). TIA and minor stroke were analyzed separately. Patients with premorbid mRS >0 were excluded. RESULTS: At 90 days, 687/3,663 (19%) patients with stroke were disabled; for TIA, 122/2,384 (5%) were disabled. In multivariate analyses, age, diabetes, and NIHSS were associated with disability in the stroke cohort, and age with disability in the TIA cohort. Postrandomization events (recurrent stroke, myocardial infarction, major bleeding, serious adverse events) were strongly associated with disability in both cohorts (stroke cohort: odds ratio [OR] 5.6, 95% confidence interval [CI] 4.5-6.9; TIA cohort: OR 14.8, 95% CI 9.9-22.0). Of the TIA patients who ended up disabled, 65% experienced a postrandomization event; for stroke patients who ended up disabled, 39% had a postrandomization event. Disability increased linearly with NIHSS score (p < 0.0001) and was greater in those with limb weakness (p < 0.0001). CONCLUSIONS: After TIA and minor stroke, subsequent stroke and medical complications are strongly associated with disability. In addition, even within a low range of baseline scores, the NIHSS is a powerful predictor of disability in minor stroke patients, with items scoring limb weakness particularly associated with subsequent disability.
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Isquemia Encefálica/complicaciones , Hemorragia/complicaciones , Ataque Isquémico Transitorio/complicaciones , Accidente Cerebrovascular/complicaciones , Anciano , Evaluación de la Discapacidad , Personas con Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paresia/complicaciones , Recurrencia , Índice de Severidad de la EnfermedadRESUMEN
RATIONALE: In patients with acute cerebral ischemia, the rate of stroke, myocardial infarction, or death during 90 days was reported to be non-significantly lower with ticagrelor compared with aspirin, with no increase in major hemorrhage. Dual antiplatelet therapy may be more effective in this setting. AIM: To investigate whether ticagrelor combined with aspirin are superior to aspirin alone in preventing stroke or death in patients with non-severe, non-cardioembolic ischemic stroke or high-risk transient ischemic attack. DESIGN: The Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death (THALES) trial is a randomized, placebo-controlled, double-blind, event-driven study. Patients will be randomized within 24 h of onset of acute ischemic symptoms. THALES is expected to randomize 13,000 at â¼450 sites worldwide, to collect 764 primary outcome events. Study treatments are ticagrelor 180 mg loading dose on day 1, then 90 mg twice daily on days 2-30, or matching placebo. All patients will also receive open-label aspirin 300-325 mg on day 1, then 75-100 mg once daily on days 2-30. STUDY OUTCOMES: The primary efficacy outcome is time to the composite endpoint of stroke or death through 30-day follow-up. The primary safety outcome is time to first severe bleeding event. DISCUSSION: The THALES trial will provide important information about the benefits and risks of dual antiplatelet therapy with ticagrelor and aspirin in patients with acute cerebral ischemia in a global setting (funding: AstraZeneca). CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov . Unique identifier: NCT03354429.
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Aspirina/administración & dosificación , Ataque Isquémico Transitorio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Accidente Cerebrovascular/tratamiento farmacológico , Ticagrelor/administración & dosificación , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Adjudication of endpoints is a standard procedure in cardiovascular clinical trials. However, several studies indicate that the benefit of adjudication in estimating treatment effect may be limited. AIMS: This post hoc analysis of SOCRATES (NCT01994720) compared the treatment effects and investigated the agreement of clinical event assessment by site investigators and independent adjudicators. METHODS: SOCRATES compared ticagrelor and aspirin in 13,199 patients with acute minor stroke or high-risk transient ischemic attack. The primary endpoint was stroke, myocardial infarction, or death. Stroke was the major component of the primary endpoint and a secondary endpoint. The endpoints were adjudicated by a blinded independent committee. We compared the treatment effect on the primary endpoint and stroke alone based on the investigators' and adjudicators' assessments, and investigated the agreement rate on the stroke endpoint and major hemorrhages. RESULTS: The hazard ratios (95% confidence interval) for ticagrelor versus aspirin therapy for the primary endpoint were 0.89 (0.78-1.01) when calculated on adjudicator-assessed events and 0.88 (0.78-1.00) for investigator-assessed events. The hazard ratios (95% confidence intervals) for stroke were 0.86 (0.75-0.99) based on the adjudicators' diagnoses and 0.85 (0.75-0.97) based on the investigators' diagnoses. The overall agreement between adjudicator- and investigator-diagnosed stroke was 91%, and for major hemorrhages was 88%. CONCLUSIONS: In SOCRATES, there was no clinically meaningful difference in the estimated treatment effect, on either the primary endpoint or stroke, by using investigator- or adjudicator-assessed events. Double-blind treatment outcome studies with stroke endpoints may not benefit from adjudication. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01994720.