Effects of Switching From Cigarettes to Tobacco Heating System on Coronary Atherosclerosis Progression

Study Overview
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Brief Summary
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Objective: To evaluate the impact of heated versus combustion tobacco products on progression of atherosclerosis in patients with CAD unable(unwilling) to quit smoking. Rationale: Despite the efforts to curb smoking and full awareness of its deleterious health impact, smoking remains a significant contributor to morbidity and mortality. Some health impact of smoking may be improved by other forms of cigarettes than traditional combustion, especially for subjects unwilling or unable to stop smoking. As recently as 2020, one of heated tobacco products (HTP)(IQOS) was FDA Authorized as a 'Reduced Exposure' product. The available evidence to date allows to conclude that the IQOS system heats tobacco but does not burn it, which significantly reduces the production of harmful and potentially harmful chemicals. Scientific studies have shown that switching completely from conventional cigarettes to the IQOS system significantly reduced body's exposure to harmful or potentially harmful chemicals. There is also evidence indicating lower levels of inflammatory markers and improved vascular function associated with use of heated tobacco products. However, it is unknown whether the reduction in the exposure translates into potential reduction of harm within cardiovascular system, as compared to the traditional (combustion) cigarettes. The evidence is of crucial importance for patients with cardiovascular diseases, medical community, and national health authorities planning evidence based policies regarding HTP/cigarettes.

Detailed Description
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Objective: To evaluate the impact of heated versus combustion tobacco products on progression of atherosclerosis in patients with CAD unable(unwilling) to quit smoking. Background Despite the efforts to curb smoking and full awareness of its deleterious health impact, smoking remains a significant contributor to morbidity and mortality. Some health impact of smoking may be improved by other forms of cigarettes than traditional combustion, especially for subjects unwilling or unable to stop smoking. As recently as 2020, one of heated tobacco products (HTP)(IQOS) was FDA Authorized as a 'Reduced Exposure' product. The available evidence to date allows to conclude that the IQOS system heats tobacco but does not burn it, which significantly reduces the production of harmful and potentially harmful chemicals. Scientific studies have shown that switching completely from conventional cigarettes to the IQOS system significantly reduced body's exposure to harmful or potentially harmful chemicals. There is also evidence indicating lower levels of inflammatory markers and improved vascular function associated with use of heated tobacco products. However, it is unknown whether the reduction in the exposure translates into potential reduction of harm within cardiovascular system, as compared to the traditional (combustion) cigarettes. The evidence is of crucial importance for patients with cardiovascular diseases, medical community, and national health authorities planning evidence based policies regarding HTP/cigarettes. Methods: Prospective, single-centre, open-label, randomised study including 180 stable patients with coronary artery disease (CAD) as diagnosed on CCTA, without indications for invasive treatment, unable(unwilling) to quit smoking, randomised 1:1 to either heated (group H) or combustion (group C) tobacco products and followed for 18 months. The follow-up is accomplished with CCTA scan. The study clinical visits are planned at 1, 3, 6, 12, and 18 months. The primary outcome is change in non calcified plaque volume at 18 months between H and C groups (intention to treat design).

Official Title
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Effects of Switching From Cigarettes to Tobacco Heating System on Coronary Atherosclerosis Progression in Patients With Stable Coronary Artery Disease

Conditions
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Coronary Artery Disease, Coronary Atherosclerosis, Nicotine Dependence

Intervention / Treatment
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* Behavioral: heated tobacco - lifestyle intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged >18 years and <75 years Subjects with stable chronic coronary syndrome defined as the presence of at least one coronary artery stenosis >=20% due to coronary plaque visible on coronary computed tomography angiography (CCTA), in an artery with a reference diameter > 2.0mm History of smoking pack-years ≥10 (Pack-years will be calculated by taking the average number of cigarettes smoked per day divided by 20 and multiplied by the number of years smoked), based on self-reporting Current smokers with a minimum of self-reported current smoking pattern of >10 cigarettes/day during the last 6 months prior to screening, smoking status will be verified based on a urinary cotinine test (cotinine ≥200 ng/mL) Patients that have been advised to quit smoking and informed of a smoking risk and cessation programs (per local SOC) and who are still not willing to set a quit date within the next 30 days at screening Stable treatment for coronary atherosclerosis according to the guidelines Have understood the study and have signed informed consent Exclusion Criteria: Any acute cardiovascular event (i.e. ACS, MI, Stroke, TIA, Limb ischemia), unstable angina or revascularization within 30 days prior to screening Planned coronary intervention (PCI, CABG) at screening Previous CABG Preexisting heart failure with reduced ejection fraction (EF <50%) Severe uncontrolled hypertension (at the discretion of investigator) Diabetes Subjects with documented genetic familial hypercholesterolemia Subjects have known serious infection or chronic inflammatory systemic disease (e.g. rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis) Subjects have a known non-cardiovascular disease that is associated with poor prognosis (e.g. metastatic cancer) Patient with currently active cancer or history of cancer within the last 5 years Subjects have hypersensitivity or any other warnings listed in the local labeling for THS Subjects have hypersensitivity to imaging iodine contrast agents GFR<45 ml/min/1,73 m2 Subjects who could not participate for any reason other than medical (e.g., psychological and/or social reason) per Investigator's judgment Subjects have any other clinical condition that would jeopardize the subject's safety while participating in this study, per Investigator's judgment Female subject is pregnant or breast-feeding, or planning to become pregnant during the study Subjects have previously participated in this study, or in an interventional study (drug or medical device) within 30 days of screening (participation in observational studies/registries allowed) Subjects have a close affiliation with the investigational site: a close relative of the investigator, a person dependent on the investigational site (e.g. employee or student of the investigational site) Subjects are current or former employee of the tobacco industry or their first-degree relatives (parent, child, spouse)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: combustion tobacco<br> | |
| Experimental: heated tobacco<br> | Behavioral: heated tobacco - lifestyle intervention<br>* Patients unable (unwilling) to stop smoking will be randomized to either combustion (C) or heated (H) tobacco groups.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in non calcified plaque volume between H and C groups (intention to treat) | CCTA based evaluation | 0-18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total plaque volume | CCTA based evaluation | 0-18 months | 
| Change in plaque volume components (low attenuation, fibrous-fatty, fibrous, non-calcified plaque, calcified plaque) | CCTA based evaluation | 0-18 months | 
| Change in non calcified plaque volume between H and C groups (as treated) | CCTA based evaluation | 0-18 months | 
| Change in lipid metabolism | Total cholesterol (TC) Triglycerides (TG) Lipoproteins: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) Apolipoproteins: apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) Lipoprotein(a) Lp(a) | 0-18 months | 
| Change in oxidative stress | 8-Epi prostaglandin F2 alpha (8 epi PGF2α) Myeloperoxidase (MPO) | 0-18 months | 
| Change in inflammation | High-sensitivity C-reactive protein (hs CRP) White blood cell (WBC) counts Homocysteine Interleukins (IL-6) Fibrinogen | 0-18 months | 
| Change in platelet activation | 11-dehydro-thromboxane B2 (11 DTX B2) Plasminogen activator inhibitor-1 (PAI-1) Tissue plasminogen activator (t-PA) Platelet count Mean platelet volume (MPV) | 0-18 months | 
| Change in endothelial dysfunction | P-selectin Metalloproteinase 9 (MMP-9) | 0-18 months | 
| Change in haemodynamic stress | N-terminal pro b-type natriuretic peptide (NT-proBNP) | 0-18 months | 
| Change in myocardial injury | high-sensitivity troponin T (hs-TnT) | 0-18 months | 
| Change in glycemia control | Fasting Blood Glucose, HbA1c | 0-18 months | 
| Change in physical activity | self reported, mobile device monitoring | 0-18 months | 
| Change in exposure to nicotine | 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol , Nicotine equivalents in spot urine , 2-cyanoethylmercapturic acid | 0-18 months | 
| SAFETY (ADVERSE OUTCOMES) | Independent DSMB will evaluate the outcomes | 0-18 months | 
| Change in self reported product use |  | 0-18 months | 
| Change in quality of life | EQ5D-5L | 0-18 months | 
| Cost/effectiveness analysis |  | 0-18 months | 
| Subgroup analysis (AGE/SEX/CO-MORBIDITIES) |  | 1-18 months |