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Bleeding complications after acute coronary syndrome with special reference to intracranial hemorrhage
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2021. , p. 73
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2107
Keywords [en]
Acute myocardial infarction, serious bleeding, intracranial hemorrhage hemorrhagic stroke
National Category
Clinical Medicine
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-178750ISBN: 978-91-7855-369-3 (print)ISBN: 978-91-7855-370-9 (electronic)OAI: oai:DiVA.org:umu-178750DiVA, id: diva2:1521533
Public defence
2021-02-19, Hörsalen Musslan, Östersunds sjukhus, Östersund, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2021-01-29 Created: 2021-01-23 Last updated: 2021-12-06Bibliographically approved
List of papers
1. Hemorrhagic stroke the first 30 days after an acute myocardial infarction: incidence, time trends and predictors of risk
Open this publication in new window or tab >>Hemorrhagic stroke the first 30 days after an acute myocardial infarction: incidence, time trends and predictors of risk
Show others...
2014 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 176, no 1, p. 133-138Article in journal (Refereed) Published
Abstract [en]

Background/objectives: Hemorrhagic stroke is a rare but serious complication after an acute myocardial infarction (AMI). The aims of our study were to establish the incidence, time trends and predictors of risk for hemorrhagic stroke within 30 days after an AMI in 1998-2008. Methods: We collected data from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA). All patients with a myocardial infarction 1998-2008 were included, n = 173,233. The data was merged with the National Patient Register in order to identify patients suffering a hemorrhagic stroke. To identify predictors of risk we used Cox models. Results: Overall the incidence decreased from 0.2% (n = 94) in 1998-2000 to 0.1% (n = 41) in 2007-2008. In patients with ST-elevation myocardial infarction the corresponding incidences were 0.4% (n = 76) in 1998-2000 and 0.2% (n = 21) in 2007-2008, and after fibrin specific thrombolytic treatment 0.6% and 1.1%, respectively, with a peak of 1.4% during 2003-2004. In total 375 patients (0.22%) suffered a hemorrhagic stroke within 30 days of the AMI. The preferred method of reperfusion changed from thrombolysis to percutaneous coronary intervention (PCI). Older age (hazard ratio (HR) >65- <= 75 vs <= 65 years 1.84, 95% confidence interval (CI) 1.38-2.45), thrombolysis (HR 6.84, 95% CI 5.51-8.48), history of hemorrhagic stroke (HR 12.52, CI 8.36-18.78) and prior hypertension (HR 1.52, CI 1.23-1.86) independently predicted hemorrhagic stroke within 30 days. Conclusions: The rate of hemorrhagic stroke within 30 days of an AMI has decreased by 50% between 1998 and 2008. The main reason is the shift in reperfusion method from thrombolysis to PCI. 

Keywords
Myocardial infarction, Hemorrhagic stroke, Time trend, Predictor
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-93472 (URN)10.1016/j.ijcard.2014.07.032 (DOI)000341040900030 ()2-s2.0-84906314668 (Scopus ID)
Available from: 2015-02-02 Created: 2014-09-23 Last updated: 2024-03-18Bibliographically approved
2. Incidence, Time Trends, and Predictors of Intracranial Hemorrhage During Long-Term Follow-up After Acute Myocardial Infarction
Open this publication in new window or tab >>Incidence, Time Trends, and Predictors of Intracranial Hemorrhage During Long-Term Follow-up After Acute Myocardial Infarction
2015 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 4, no 12, article id e002290Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: To address the lack of knowledge regarding the long-term risk of intracranial hemorrhage (ICH) after acute myocardial infarction (AMI), the aims of this study were to: (1) investigate the incidence, time trends, and predictors of ICH in a large population within 1 year of discharge after AMI; (2) investigate the comparative 1-year risk of ICH in AMI patients and a reference group; and (3) study the impact of previous ischemic stroke on ICH risk in patients treated with various antithrombotic therapies.

METHODS AND RESULTS: Data about patients whose first AMI occurred between 1998 and 2010 were collected from the Swedish Register of Information and Knowledge about Swedish Heart-Intensive-Care Admissions (RIKS-HIA). Patients with an ICH after discharge were identified in the National Patient Register. Risk was compared against a matched reference population. Of 187 386 patients, 590 had an ICH within 1 year. The 1-year cumulative incidence (0.35%) was approximately twice that of the reference group, and it did not change significantly over time. Advanced age, previous ischemic or hemorrhagic stroke, and reduced glomerular filtration rate were associated with increased ICH risk, whereas female sex was associated with a decreased risk. Previous ischemic stroke did not increase risk of ICH associated with single or dual antiplatelet therapy, but increased risk with anticoagulant therapy.

CONCLUSION: The 1-year incidence of ICH after AMI remained stable, at ≈0.35%, over the study period. Advanced age, decreased renal function, and previous ischemic or hemorrhagic stroke are predictive of increased ICH risk.

Keywords
acute myocardial infarction, intracranial hemorrhage, ischemic stroke
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-116995 (URN)10.1161/JAHA.115.002290 (DOI)000369947700016 ()26656860 (PubMedID)2-s2.0-85006184273 (Scopus ID)
Available from: 2016-02-17 Created: 2016-02-17 Last updated: 2023-03-24Bibliographically approved
3. Increased Use of Ticagrelor After Myocardial Infarction Is Not Associated With Intracranial Hemorrhage: Results From a Nationwide Swedish Registry
Open this publication in new window or tab >>Increased Use of Ticagrelor After Myocardial Infarction Is Not Associated With Intracranial Hemorrhage: Results From a Nationwide Swedish Registry
2018 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 12, p. 2877-2882Article in journal (Refereed) Published
Abstract [en]

Background and Purpose: Guidelines recommend dual antiplatelet treatment with ticagrelor instead of clopidogrel after acute myocardial infarction. Ticagrelor increases major and minor noncoronary artery bypass graft bleeding compared with clopidogrel, but whether the risk of intracranial hemorrhage (ICH) increases is unknown. We aimed to examine any association between ticagrelor and ICH and to identify predictors of ICH among unselected patients after acute myocardial infarction.

Methods: Patients with acute myocardial infarction were identified using the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions, and the data were combined with the Swedish National Patient Registry to identify ICH occurrence. To avoid obvious selection bias related to the choice of dual antiplatelet treatment, we divided the study cohorts into 2 time periods of similar length using the first prescription of ticagrelor as a cutoff point (December 20, 2011). The risk of ICH during the first period (100% clopidogrel treatment) versus the second period (52.1% ticagrelor and 47.8% clopidogrel treatment) was assessed using Kaplan-Meier analysis. Cox proportional-hazards regression analyses, with assessment of interactions between all significant variables, were used to identify predictors of ICH.

Results: The analysis included 47 674 patients with acute myocardial infarction. The cumulative incidence of ICH during the first period was 0.59% (91 cases [95% CI, 0.49-0.69]) versus 0.52% (97 cases [95% CI, 0.43-0.61]) during the second period (P=0.83). In multivariable Cox analysis, study period (second versus first period) was not predictive of ICH. Interaction analyses showed that age and prior cardiovascular morbidities were of importance in predicting the risk of ICH.

Conclusions: The increased use of ticagrelor was not associated with ICH, whereas age and prior cardiovascular morbidities were related to the risk of ICH and interacted significantly.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
Keywords
acute coronary syndrome, intracranial hemorrhages, myocardial infarction, purinergic P2Y receptor tagonists, risk factors
National Category
Cardiac and Cardiovascular Systems Neurology
Identifiers
urn:nbn:se:umu:diva-156336 (URN)10.1161/STROKEAHA.118.022970 (DOI)000456427700025 ()30571411 (PubMedID)2-s2.0-85058925046 (Scopus ID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2023-03-24Bibliographically approved
4. Bleeding after acute coronary syndrome: incidence and predictors during long-term follow-up in a population-based cohort study
Open this publication in new window or tab >>Bleeding after acute coronary syndrome: incidence and predictors during long-term follow-up in a population-based cohort study
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-179100 (URN)
Available from: 2021-01-25 Created: 2021-01-25 Last updated: 2021-01-25

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