Ischemic Benefit and Hemorrhage Risk of Ticagrelor-Aspirin Versus Aspirin in Patients With Acute Ischemic Stroke or Transient Ischemic Attack.

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.

Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes).

BACKGROUND: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). METHODS: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. RESULTS: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52-1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. CONCLUSIONS: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720.

Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome--a randomised controlled trial.

We have previously conducted a small treatment study on staphylococcus toxoid in fibromyalgia (FM) and chronic fatigue syndrome (CFS). The aim of the present study was to further assess the efficacy of the staphylococcus toxoid preparation Staphypan Berna (SB) during 6 months in FM/CFS patients. One hundred consecutively referred patients fulfilling the ACR criteria for FM and the 1994 CDC criteria for CFS were randomised to receive active drug or placebo. Treatment included weekly injections containing 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml, 0.9 ml, and 1.0 ml SB or coloured sterile water, followed by booster doses given 4-weekly until endpoint. Main outcome measures were the proportion of responders according to global ratings and the proportion of patients with a symptom reduction of > or =50% on a 15-item subscale derived from the comprehensive psychopathological rating scale (CPRS). The treatment was well tolerated. Intention-to-treat analysis showed 32/49 (65%) responders in the SB group compared to 9/49 (18%) in the placebo group (P<0.001). Sixteen patients (33%) in the SB group reduced their CPRS scores by at least 50% compared to five patients (10%) in the placebo group (P< 0.01). Mean change score on the CPRS (95% confidence interval) was 10.0 (6.7-13.3) in the SB group and 3.9 (1.1-6.6) in the placebo group (P<0.01). An increase in CPRS symptoms at withdrawal was noted in the SB group. In conclusion, treatment with staphylococcus toxoid injections over 6 months led to significant improvement in patients with FM and CFS. Maintenance treatment is required to prevent relapse.

A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale).

OBJECTIVE: To construct an observer's rating scale sensitive to change for measuring severity and treatment outcome in fibromyalgia (FM) and chronic fatigue syndrome (CFS) patients. METHODS: A selection of items from the Comprehensive Psychopathological Rating Scale (CPRS) were repeatedly rated and used as outcome measure of a 24-week treatment study. In the study 100 women, fulfilling the criteria for both FM and CFS, received intermittent injections of a staphylococcus toxoid or placebo. Nine CPRS-items with high baseline incidence (cutoff 70%) were extracted and validated against global ratings and the Fibromyalgia Impact Questionnaire (FIQ). The fibromyalgia and chronic fatigue syndrome rating scale (the FibroFatigue scale) was thereafter formed based upon the extracted items and three supplemented ones. The interrater reliability was tested in 27 consecutive patients of both sexes. RESULTS: The FibroFatigue scale is an observer's rating scale with 12 items measuring pain, muscular tension, fatigue, concentration difficulties, failing memory, irritability, sadness, sleep disturbances, and autonomic disturbances (items derived from the CPRS) and irritable bowel, headache, and subjective experience of infection (new items). There was a statistically significant correlation between the CPRS-extracted items and global ratings as well as with the FIQ. The interrater reliability of the new scale was excellent (correlation coefficient.98), irrespective of the patients' gender. CONCLUSION: The FibroFatigue scale seems to be a reliable and valid measuring instrument with capacity to monitor symptom severity and change during treatment of FM/CFS patients.