Bleeding complications after acute coronary syndrome with special reference to intracranial hemorrhage

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.