Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin ...improves outcomes in this population is unclear.
In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.
A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval CI, 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P = 0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P = 0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).
In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).
The control of confounding is an area of extensive epidemiological research, especially in the field of causal inference for observational studies. Matched cohort and case-control study designs are ...commonly implemented to control for confounding effects without specifying the functional form of the relationship between the outcome and confounders. This paper extends the commonly used regression models in matched designs for binary and survival outcomes (i.e. conditional logistic and stratified Cox proportional hazards) to studies of continuous outcomes through a novel interpretation and application of logit-based regression models from the econometrics and marketing research literature. We compare the performance of the maximum likelihood estimators using simulated data and propose a heuristic argument for obtaining the residuals for model diagnostics. We illustrate our proposed approach with two real data applications. Our simulation studies demonstrate that our stratification approach is robust to model misspecification and that the distribution of the estimated residuals provides a useful diagnostic when the strata are of moderate size. In our applications to real data, we demonstrate that parity and menopausal status are associated with percent mammographic density, and that the mean level and variability of inpatient blood glucose readings vary between medical and surgical wards within a national tertiary hospital. Our work highlights how the same class of regression models, available in most statistical software, can be used to adjust for confounding in the study of binary, time-to-event and continuous outcomes.
The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease ...(SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.
•Ticagrelor did not reduce the composite end point of vaso-occlusive crises; there was no evidence of efficacy across secondary end points.•Ticagrelor should not be used for the prevention of vaso-occlusive crises in pediatric patients with SCD.
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Ticagrelor reduced major adverse cardiovascular events (MACE) and increased bleeding in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease. Limb events including ...revascularization, acute limb ischemia (ALI), and amputation are major morbidities in patients with T2DM and atherosclerosis.
This study sought to determine the effect of ticagrelor on limb events.
Patients were randomized to ticagrelor or placebo on top of aspirin and followed for a median of 3 years. MACE (cardiovascular death, myocardial infarction, or stroke), limb events (ALI, amputation, revascularization), and bleeding were adjudicated by an independent and blinded clinical events committee. The presence of peripheral artery disease (PAD) was reported at baseline.
Of 19,220 patients randomized, 1,687 (8.8%) had PAD at baseline. In patients receiving placebo, PAD was associated with higher MACE (10.7% vs 7.3%; HR: 1.48; P < 0.001) and limb (9.5% vs 0.8%; HR: 10.67; P < 0.001) risk. Ticagrelor reduced limb events (1.6% vs 1.3%; HR: 0.77; 95% CI: 0.61-0.96; P = 0.022) with significant reductions for revascularization (HR: 0.79; 95% CI: 0.62-0.99; P = 0.044) and ALI (HR: 0.24; 95% CI: 0.08-0.70; P = 0.009). The benefit was consistent with or without PAD (HR: 0.80; 95% CI: 0.58-1.11; and HR: 0.76; 95% CI: 0.55-1.05, respectively; Pinteraction = 0.81). There was no effect modification of ticagrelor vs placebo based on PAD for MACE (Pinteraction = 0.40) or TIMI major bleeding (Pinteraction = 0.3239).
Patients with T2DM and atherosclerosis are at high risk of limb events. Ticagrelor decreased this risk, but increased bleeding. Future trials evaluating the combination of ticagrelor and aspirin would further elucidate the benefit/risk of such therapy in patients with PAD, including those without coronary artery disease. (A Study Comparing Cardiovascular Effects of Ticagrelor Versus Placebo in Patients With Type 2 Diabetes Mellitus THEMIS: NCT01991795)
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This study aims to contribute with knowledge about preschool teachers’ perspectives on documentation in the systematic quality work. The study uses a qualitative method where the collected empirical ...evidence is based on answers from 10 interviewed preschool teachers. The study is based on a phenomenographic method and the process of the analysis is based on post-constructionist theory. The result of the study shows that the preschool teachers describe two different ways to look at the purpose of documentation. One way described was to see the documentation as an important tool to acknowledge the children’s processes of learning and for the preschool teachers to see their own actions to further develop their profession. The other way, according to some preschool teachers, was to document for others. The preschool teachers described how they followed and documented each child's learning and development differently. Some preschool teachers expressed that the documentation was linked to projects and themes. Other preschool teachers, as the study interprets, follow and document the children through the stages of their development. The result of the analysis of documentation showed that some of the preschool teachers reflected and analyzed together with their team of co-workers. Many of the preschool teachers involved the children in the reflections while some of the preschool teachers did not analyze the documentation at all. Our conclusion is that there is a difference between how preschool teachers think and work with their documentation depending on their practical conditions, for example, time and competence.
Studiens syfte var att bidra med kunskap om förskollärares perspektiv på dokumentation i det systematiska kvalitetsarbetet. Studien är av en kvalitativ metod där vår insamlade empiri består av svar från 10 intervjuade förskollärare. Studien bygger på en fenomenografisk metodansats och vi har utgått ifrån ett postkonstruktionistisk teoretiskt perspektiv i vår analysprocess. Studiens resultat visar på att förskollärarna har olika uppfattningar som genererade i två skilda sätt att se på syftet med dokumentationen. Det ena var att förskollärarna uttryckte att dokumentationen var ett viktigt redskap för att få syn på barns lärprocesser och att förskollärarna kunde använda dokumentationerna för att få syn på sitt eget agerande, för att kunna vidareutveckla sin profession. Det andra skilda sättet som några förskollärare ansåg, var att dokumentera för andra. Förskollärarna beskrev olika kring hur de följde och dokumenterade varje barns lärande och utveckling. En del förskollärare gav uttryck att dokumentationen var kopplad till projekt och teman. Andra förskollärare tolkar vi att de följer och dokumenterar barn utifrån deras utvecklingsstadier. I resultatets analys av dokumentation visade resultatet att en del av förskollärarna reflekterade och analyserade med sitt arbetslag. Många av förskollärarna involverade barnen i reflekterandet. Medan en del av förskollärarna inte analyserade dokumentationerna alls. Vår slutsats är att det är olika hur förskollärare tänker och gör med sin dokumentationer beroende på deras förutsättningar i praktiken, som exempelvis tid och kompetens.
The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced ...the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population.
The population was divided into tertiles: score ≤22, 23 to 33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (net adverse clinical events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted.
Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (Pinteraction = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (Pinteraction = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; Pinteraction = .012).
In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor.
Huvudsyftet med studien var att granska hur väl patientens och tandläkarens uppfattning om patientens kariesförekomst överensstämde. Andra syften var att jämföra patientens uppfattning om sin ...kariessituation och denna uppfattnings-korrelation med ålder, kön, utbildningsnivå och härkomst.Studien baserades på 125 ifyllda enkäter och journaluppgifter (kön, ålder, kliniska och röntgenologiska fynd av manifest och sekundärkaries) av patienter som besökte Tandvårdshögskolan i Malmö för en undersökning. Enkäterna, journaluppgifterna och röntgenbilder granskades och fylldes i ett på förhand utformat protokoll. Uppgifterna sammanställdes och grupperades för statistiska analyser, chi-2.Resultatet visade att fler kvinnor än män trodde sig har karies. Det fanns en bristande överenstämmelse mellan vad individen trodde och hur den kliniska situationen såg ut. Det var både många som trodde sig har karies som inte hade någon karies, och individer som inte trodde sig ha karies som hade karies. De vanligaste orsakerna till att individerna trodde de hade karies var att de sett eller känt att en bit av tanden saknas, att det gjorde ont eller att de känt isningar i någon tand. Signifikanta skillnader gällande kariesförekomst fanns hos de som gick eller inte gick på regelbundna undersökningar. De som inte gick på regelbundna undersökningar trodde och hade karies i större utsträckning än de som gjorde det. Det fanns inga signifikanta skillnader avseende bakgrundsfaktorerna ålder, kön, etnicitet eller utbildningsnivå i förhållande till kariesförekomsten.
The main purpose of the study was to examine how well the patient's and dentist's perception of the patient's caries occurred. Other purposes were to compare the patient's perception of caries status and this perception's correlation to age, gender, educational level and origin.The study was based on 125 completed questionnaires and journal records (gender, age, clinical and x-ray findings of manifest and secondary caries) of patients who visited the Dental Care School in Malmö for an examination. The questionnaires, journal records and x- rays were examined and filled in a pre-written protocol. The data was compiled and grouped for statistical analyzes, chi-2.The result showed that more women than men thought they had caries. There was a lack of consistency between what the individual thought and clinical findings. It was both many who thought they had caries who had no caries, and individuals who did not think they had caries that had caries. The most common reasons why the individuals thought they had caries were that they saw or felt that a piece of the tooth was missing, perception of pain or that they felt tooth sensitivity. Significant differences in caries prevalence among those who did or did not attend regular examinations. Those who did not go on regular examinations both thought that they had caries and had recorded caries to a greater extent than those who did go regularly. There were no significant differences regarding the background factors age, gender, ethnicity or level of education in relation to the caries experience.
An unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and ...vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y12 receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD.
Approximately 180 patients (aged ≥ 2 to <18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes.
HESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients.
Trial Identifier: NCT03615924; EudraCT2017-002421-38.
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