Akershus Cardiac Examination (ACE) 5 Study

Background - The pathophysiology of chronic coronary syndrome

Myocardial infarction is the number 1 cause of death among smokers. An underlying framework related to this project is the potential to detect and treat atherosclerotic cardiovascular disease (ASCVD), which primarily manifests as coronary artery disease (CAD), prior to the development of symptoms and clinical events. This is important as CAD could be an unstable condition where acute occlusion of coronary arteries will lead to immediate myocardial necrosis, which is referred to as acute myocardial infarction. Smoking is a principal risk factor for atherosclerotic plaques and later symptomatic CAD. Myocardial infarction has significant mortality, both in the acute phase and later due to post-infarction heart failure mortality as well as recurrent myocardial infarction. As many as 1/5 of all patients having a myocardial infarction experience sudden cardiac death as their first symptom. Strategies that can detect CAD prior to events that leads to symptoms (subclinical disease) is therefore highly desirable.

Background - Lung Cancer Screening Programs and risk stratification for CVD

Lung cancer screening programs represent an excellent opportunity to screen high-risk individuals for ASCVD. Non-contrast, non-cardiac chest CT is the cornerstone of lung cancer screening and performed in all lung cancer screening participants. With these CT scans, the investigators can assess coronary artery calcification (CAC) with acceptable accuracy, either by using the four-group visual score or other method, like calculating Agatston score or ordinal visual scores. Moreover, as contrast agents are not required for the cardiac assessment and there is no need for ECG-triggering or cardiac specific protocols, the CT scans will not represent any risk to participant health or put additional strain on health services performing lung cancer screening. Radiation from current CT scans for lung cancer screening is 1.5-3 mSv, which is below the background radiation.

The clinical value of CACS by both Agatston, ordinal visual scores and the four-group visual score has been demonstrated in several studies, and the investigators believe that specific characteristics of our screening population will make assessing coronary artery calcification especially valuable for identifying subclinical CAD in the ACE 5 Study population. Assessment of CAC is also recommended by the National Lipid Association and the 2016 SCCT/STR guidelines for coronary artery calcium scoring of non-contrast noncardiac chest CT scans. One caveat of using coronary artery calcification to screen for subclinical CAD in the general population has been a very small number of individuals with CACS=0 that still experience cardiovascular events during follow-up. While CAC=0 is considered the one most important negative risk factor, a study of CAC in the lung cancer screening setting with non-contrast noncardiac chest CT scans show that up to 10% of the scans with CAC=0 experienced a major cardiac event. Hence, it is suggested that when CAC is assessed in noncardiac chest CT scans, CAC=0 should not always lead to delayed or avoidance of pharmacotherapies.

Traditional risk models like SCORE 2 also has limitations. Although excellent calibrated in the general population to identify high-risk individuals, SCORE 2 (and other models) cannot separate individual subjects in a group where all met the criteria of intermediate to high risk (>7.5% risk of cardiovascular event over 10-year follow-up). Hence, in our lung cancer screening population the inclusion criteria of age 60-79 years and 35 pack years of tobacco exposure in the TIDL Study will make most participants in the ACE 5 Study classified as intermediate to high risk for future cardiovascular event. Moreover, from epidemiological studies in the same age group, the investigators found 62% of middle-aged individuals to have a diagnosis of hypertension (defined according to prior, conservative criteria with blood pressure ≥140/90 mmHg) and mean total cholesterol was 5.5 mmol/L12. Accordingly, the investigators recognize that most participants in the ACE 5 Study will be classified as at least intermediate risk for CVD, and that no further separation is possible based on the SCORE 2 risk model.

Strategies to detect and reduce risk factors for ASCVD

Identifying subclinical CAD with the visual four-group classification will only reduce cardiovascular events if one is able to reduce risk factor profile in affected individuals. Several lifestyle and pharmacological interventions are efficient to reduce disease progression in subclinical CVD. Smoking is a principal risk factor and all participants in TIDL have been offered participation in a smoking cessation program. Smoking cessation will be follow-up also in the ACE 5 Study. Additional risk factors for ASCVD include hypertension, elevated atherogenic lipids, type 2 diabetes mellitus (T2DM), and physical inactivity.

The investigators will inform participants randomized to the standard-of-care group of the results from visual four-group classification of coronary artery calcification and the clinical examination. The investigators will provide this information to the physician of the participants randomized to standard care, given that this is approved by the participant. The investigators will include key information about guideline-directed medical goals, which is also the primary endpoint of the ACE 5 Study, in the letter to the participants and relevant physicians in the standard care group. In the control group, the General Practitioner (GP) will decide treatment and activities to reduce risk factors, which is the current model for follow-up of heavy smokers in Norway.

In contrast, for the intervention group the study will test hospital-based, nurse-led follow-up, including risk stratification and risk factor intervention. This model is a copy of the Swedish model for cardiovascular follow-up which is a 12-month hospital-based ("infarkt mottagning), nurse-led ("infarkt sjöterska") follow-up. In the Swedish model, individuals normally meet nurse x 2 and physician x 1 during 12-months of follow-up. In addition, individuals are informed to contact the hospital for all pharmacological prescriptions during the 12-month period. For all patients randomized to the Lung Cancer Screening Plus Program, the research team will perform an individual multidisciplinary assessment using the risk factors of each individual together with SCORE2 and coronary artery calcification to reach a recommendation for preventive measures aimed at lipid and blood sugar modifying therapy, antihypertensive therapy, smoking cessation, and increased physical activity. At every hospital visit, close monitoring of major prevention goals for guideline-directed medical therapy (GDMT) are checked. The nurse will contact the physician if GDMT goals are not met and therapy will be intensified. Health personnel also talk to patients/ participants about symptoms, side effects, and other questions that may affect treatment adherence.

The Swedish model has proven important to increase number of individuals with optimal GDMT, including reporting 1 year after myocardial infarction that 50% of smokers have stopped smoking, 77% have reached blood pressure target, and 60% have reached cholesterol target. In contrast, less than 30% of Norwegian patients have optimal GDMT after myocardial infarction. Still, whether the Swedish model for follow-up can be transferred also to a lung cancer screening program, and whether this model provides superior results to a strong GP-based health system, are currently not known.

Rationale for the Study

Individuals with extensive smoking history have 2- to 3-fold increased risk of dying prematurely compared to age- and gender-matched peers. Historical data indicate that 55% of heavy smokers will die from atherosclerotic cardiovascular disease (CVD), while approximately 5% will die from lung cancer. Lung cancer screening programs are currently being implemented worldwide, while no screening program has been developed for CVD. To utilize lung cancer screening programs as a basis for early detection of subclinical ASCVD in heavy smokers and to implement cost-efficient systems for risk reduction, should therefore be clinically relevant.

The research group behind the ACE 5 Study are affiliated with the study team behind the implementation study of lung cancer screening in Norway ("Tidlig oppdagelse av lungekreft [TIDL]"). Inclusion criteria for the TIDL Study include age 60-79 years and 35 pack years of tobacco exposure. The inclusion criteria will categorize most participants as at least intermediate risk for CVD during the next decade. As non-contrast, non-cardiac chest CT images, obtained during regular lung cancer screening, directly can assess atherosclerotic cardiovascular burden, it is hypothesized that additions to current lung cancer screening programs concomitantly will reduce CVD risk. In short, the ACE 5 Study will invite 1000 heavy smokers for baseline characterization, including blood sampling. After initial examination, calculation of SCORE 2 and visual four-group classification of CAC, the study will randomize (A) 50% of the participants to the intervention group with hospital-based, nurse-led follow-up and (B) 50% of the participants to the control group.

Study objectives

The TIDL Study has examinations of 1000 participants with non-contrast, non-cardiac chest CT and the ACE 5 Study should be able to include approximately 500 participants in each group. Only participants with complete follow-up data after 12 months are eligible for the primary endpoint, and an additional 5-10% drop out for the second visit is to be expected. The total number of participants in each group with complete data for the primary endpoint is expected to be around 450.

Primary endpoint

To determine whether a Lung Cancer Screening Plus Program in individuals with heavy smoking history improves cardiovascular risk profile, defined as reaching treatment goals or started new GDMT for smoking, lipid concentrations, blood pressure, and HbA1c, compared to the current strategy/standard care.

Study population The ACE 5 Study will enroll a maximum of 1000 participants meeting all inclusion criteria and no exclusion criteria. Only participants that have already consented to participate in the pilot implementation study for lung cancer screening in Norway ("Tidlig oppdagelse av lungekreft [TIDL]") are eligible for inclusion in the ACE 5 Study as these individuals have non-contrast, non-cardiac chest CT images available from the lung cancer screening study.

All patients will be thoroughly informed about all aspects of the study and the study team will collect informed, written consent from all study participants. Regardless of the time, at the request by the participant and not already included in a publication, all data collected in the study relating to the particular participant will be terminated.

There will be no restrictions to the diagnostic testing of our study participants, regardless of randomization status in the study. The decision of the patient to participate in the ACE 5 Study will not influence treatment that is offered to the patient at Akershus University Hospital and patients not participating in the study will receive current strategy/ standard care.