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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).