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- Graipe, Anna, 1973-
(author)
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Bleeding complications after acute coronary syndrome with special reference to intracranial hemorrhage
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Background: Bleeding complications following acute coronary syndrome (ACS) have attracted considerable attention in recent years. The gradual implementation of new evidence-based treatments in patients with ACS, with a focus on anti-ischemic therapy, has reduced the risk of ischemic events (new myocardial infarction or ischemic stroke) but at the expense of increased bleeding risk. Bleeding is associated with both increased morbidity and mortality and, with major bleeding, the risk of death is comparable to that seen in myocardial infarction. Avoidance of bleeding is one possible way to further improve post-ACS outcomes. During the 1990s reperfusion approaches shifted from thrombolysis, with its increased risk of bleeding and intracranial hemorrhage (ICH), to percutaneous coronary intervention (PCI), with an expected lower risk. Treatment recommendations are derived from randomized controlled trials in which high-risk patients are excluded, and observational studies are needed to assess outcomes. Antithrombotic treatment is associated with increased risk of serious bleeding and even more so with the new potent P2Y12 inhibitors. However, their association with ICH is not well studied, and knowledge is limited regarding temporal trends in ICH after ACS. Furthermore, few studies have long-term follow-up for serious bleedings and associated risk factors.Aims: The aims of this thesis were to assess the incidence, temporal trends and factors associated with ICH after acute myocardial infarction (AMI); investigate the impact on ICH risk of changing the treatment regimen from clopidogrel to ticagrelor; estimate the risk of serious bleeding (bleeding requiring hospitalization) after ACS and characterize the type of bleeding; identify factors associated with increased bleeding risk; and assess if serious bleeding is associated with increased mortality. Method: In studies I–III, patients with AMI were identified using the Register of Information and Knowledge About Swedish Heart Intensive Care Admission (RIKS-HIA), and the data were combined with information from the Swedish National Patient Register, 1998–2013 to identify ICH. In study II, we included a matched reference group from Statistics Sweden. Study IV included all patients who were identified with an ACS during the inclusion period of the Nurse-Based Age-Independent Intervention to Limit Evolution of Disease After Acute Coronary Syndrome risk factor trial (2010–2014), and patients were followed until December 2017. Serious bleedings were identified in the local diagnosis registry, and scrutinizing of the medical records validated all diagnoses. Baseline characteristics in all studies were evaluated using the student t-test, Mann–Whitney U test, or the chi-square test as appropriate. In studies I and II, the observational time was divided into periods and in study I the chi-square test for trend was used to evaluate the trend over time. Temporal trends in study II were assessed by Kaplan–Meier analysis and evaluated using log-rank test. To reduce selection bias related to the choice of antiplatelet treatment in study III, the date of the first prescription of ticagrelor was identified in the RIKS-HIA registry and used as a cutoff point, and the study period was divided into two periods of similar length to create two cohorts. The risk in the first with respect to the second cohort was assessed by Kaplan–Meier analysis, and cohorts were compared with the log-rank test. Kaplan–Meier analysis was also used in study IV to assess serious bleeds. Predictors were assessed by Cox regression analyses. Results: The 30-day risk of hemorrhagic stroke decreased from 0.2% in 1998 to 0.1% in 2008. The decrease can be explained by the shift in reperfusion method from thrombolysis to PCI in patients with a ST-elevation myocardial infarction. Age, hypertension and previous hemorrhagic stroke were associated with increased risk. The cumulative incidence of ICH within one year of AMI was 0.35%, which did not change during the 13-year follow-up (1998–2010) despite a considerable increase in the use of dual antiplatelet therapy. The incidence of ICH in the AMI cohort was twice that of a matched reference group. Age, decreased kidney function and previous ischemic and hemorrhagic stroke were associated with increased ICH risk. None of the medications included in the analysis were associated with a significant change in ICH risk. For antiplatelets, ticagrelor is a more potent P2Y12 inhibitor compared to clopidogrel and has previously been associated with increased bleeding risk; however, in this work ticagrelor was not associated with increased risk of ICH compared to clopidogrel. In study IV, during a median follow-up of 4.6 years, 8.6% of patients had a serious bleed after their ACS. This rate was 13.4% in patients aged ≥75 years. The most common location was gastrointestinal, followed by ICH. Risk factors associated with serious bleeding were age ≥75 years, hypertension, and previous heart failure. Bleeding per se was not associated with increased mortality.Conclusion: The shift in reperfusion method from thrombolysis to PCI likely explained the decrease in ICH in the acute phase after an AMI. The incidence of ICH post-discharge was stable over the study period despite increased use of antithrombotic therapy, and the use of more potent P2Y12 inhibitor did not increase the ICH risk. Serious bleeding was relatively frequent in the long term after ACS, and bleeding recurrence was common. Important risk factors for bleeding were age, hypertension, previous ischemic or hemorrhagic stroke, decreased renal function and previous heart failure. Individualized assessment of risk factors and comorbidity and individualized intensity and duration of antithrombotic treatment may further improve outcome in ACS patients. Continuous re-evaluation of bleeding risk is needed.
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- Henriksson, Robin, 1986-
(author)
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Secondary prevention after acute coronary syndrome : antiplatelet therapy and risk factor control
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Background: One of the leading causes of death and disability worldwide is cardiovascular disease (CVD), including acute myocardial infarction (AMI). Despite improvements in medical treatment, management, and care over the years and the halving of mortality in recent decades, there is considerable room for improvement. Following myocardial infarction (MI), a patient is at great risk for subsequent infarctions or other related complications. In addition, the risk of ischemic stroke is increased following MI. Secondary prevention after MI is paramount for reducing further complications and consists of lifestyle changes, optimised medical treatment, and risk factor control of blood pressure (BP) and blood lipid levels. Although secondary preventive measures are effective, the proportion of patients reaching set treatment target levels is disappointingly low.Most patients are prescribed dual antiplatelet therapy (DAPT) following MI as part of their secondary preventive treatment. Several articles have been published on treatment efficacy based on comparisons with different kinds of antiplatelet drugs and in different combinations. However, little data specifically address the incidence of ischemic stroke after MI in real-world populations. In addition to antiplatelet treatment, secondary prevention comprises risk factor control of hypertension and hyperlipidaemia. Given the low proportion of patients reaching set target levels for BP and blood lipids, new strategies are needed.Aims: The aim of this dissertation is partly to elucidate if the rapid change in preferred DAPT in Sweden, from clopidogrel to ticagrelor in addition to aspirin, affected the incidence of ischemic stroke in patients suffering AMI (paper I) and in patients suffering AMI who have a history of ischemic stroke (paper II).The second part of the dissertation aims to investigate the feasibility and implementation of a randomised controlled trial of a nurse-led telephone-based secondary preventive program, and to assess the proportion of patients who can be included in an unselected acute coronary syndrome (ACS) population (paper III). Furthermore, the aim of the trial was to assess the long term results regarding systolic BP (SBP), diastolic BP (DBP), and low-density lipoprotein cholesterol (LDL-C) after 36 months of intervention and follow-up compared to a control group receiving usual care (paper IV).Methods: Papers I and II examined the impact of a change in the antiplatelet regimen following MI in regard to ischemic stroke occurrence. Data were obtained from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (i.e., RIKS-HIA). The register was combined with the National Patient Register (NPR) and the Cause of Death Register (CDR) in order to obtain data on stroke occurrence. Patients with AMI and treated with either clopidogrel or ticagrelor were assigned to one of two cohorts, each covering a 2- year time period, with the initial prescription of ticagrelor (20 Dec 2011) used as a cutoff point. Patients in the early cohort (n=23,447) were treated exclusively with clopidogrel, whereas those in the later cohort (n=24,227) were treated with either clopidogrel (47.9%) or ticagrelor (52.1%). In paper II, the same methodology was used, but with a study sample restricted to AMI patients with a history of ischemic stroke. In paper II, there were 1633 patients in the early cohort and 1642 in the late cohort. In the late cohort, 66.3% patients were treated with clopidogrel and 33.7% with ticagrelor. Kaplan–Meier analysis was used to assess the risk of ischemic stroke over time, with multivariable Cox regression analysis used to identify predictors of ischemic stroke. Nurse-based Age independent Intervention to Limit Evolution of Disease (Papers III and IV were based on the NAILED)-ACS trial. The NAILED-ACS trial was an open randomised controlled trial of whether a nurse-led telephone-based follow-up and medical titration after MI or unstable angina achieved lower levels of BP and LDL-C than usual care. In paper III, patients admitted for ACS during January 2010 and December 2013 were evaluated for participation. Factors predicting participation and non- participation were assessed using logistic regression. Mortality rates after one year among included and excluded patients and patients declining participation were assessed using Kaplan–Meier analysis. For paper IV, all patients admitted with ACS at Östersund Hospital between January 2010 and December 2014 were screened for inclusion based on their ability to participate in a telephone- based follow-up. Participants were randomised into two parallel groups, an intervention group and a control group receiving usual care. BP and LDL-C were measured at 1, 12, 24, and 36 months. The baseline consisted of randomised patients who completed the one-month follow-up. The intervention group received counselling and medical titration to attain treatment targets (BP <140/<90 mmHg and LDL-C <2.5/<1.8 mmol/L). Adjusted means stratified by sex and type of ACS were calculated for SBP and DBP and LDL-C. The proportion of patients who achieved treatment target levels at the end of the study was also assessed.Results: Among the general AMI population treated with either clopidogrel or ticagrelor, the incidence of ischemic stroke after one year was 2.8% in the early cohort vs. 2.4% in the late cohort (p=0.001) (paper I). The study population in paper II, in which all patients had a history of previous ischemic stroke, was overall older and had a higher prevalence of comorbidities than the population in paper I. In paper II, incidence of ischemic stroke in the early cohort was 12.1% vs. 8.6% in the late cohort (p<0.01). Corresponding incidence of intracranial bleeding for the population in paper II was a non-significant 1.2% vs 1.5%.In the feasibility study of the NAILED-ACS trial (paper III), 907 patients were assessed for inclusion. Among these, 72.9% could be included (n=661), 146 patients (16.1%) were excluded, and 100 patients declined participation (11 %). Reasons for exclusion were mainly participation in another trial, dementia, inability to use a telephone, and advanced disease. Examples of predictors of both exclusion and declining participation were older age, lower functional status, and lower education. Non-participating patients had significantly higher mortality rates at one year compared to participating patients.Paper IV presents the final results of the NAILED-ACS risk factor trial in which a total of 962 patients were randomised and completed the one-month follow- up. Of this group, 797 were available for analysis after 36 months. Compared to the control group, in the intervention group, mean SBP was 4.1 mmHg lower, mean DBP was 2.9 mmHg lower, and mean LDL-C was 0.28 mmol/L lower (p<0.001 for all). The proportions of patients reaching treatment target goals for SBP, DBP, and LDL-C were significantly higher in the intervention group. In regard to SBP, 77.6% of intervention patients achieved treatment target levels, compared to 62.9% in the control group. Corresponding numbers for DBP were 90.9% vs. 80.8% and for LDL-C, they were 65.6% vs. 53.1%Conclusion: The incidence of ischemic stroke was significantly lower in a cohort of AMI patients following a change in preferred treatment from clopidogrel to ticagrelor (paper I). In AMI patients with a history of ischemic stroke (paper II), the incidence rate of ischemic stroke was significantly lower in the late cohort compared to the early cohort, and overall incidence rates were markedly higher than in paper I.The NAILED-ACS trial was shown to be both feasible (paper III) and successful, with a higher proportion of patients reaching treatment target levels in the intervention group, and significantly lower mean values for SBP, DBP, and LDL- C (paper IV).
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