Clinical trial NCT03863509: E-Cigarette Effects on Markers of Cardiovascular and Pulmonary Disease
Official title: E-Cigarette Effects on Markers of Cardiovascular and Pulmonary Disease Risk (Aka CLUES - Cardiac and Lung E-cig Smoking Study)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tobacco Use
E-Cigarette Use
Cardiovascular Diseases
Pulmonary Disease
Keywords: vape
E-Cigarette
E-cig
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2019-03-05
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 165 exclusive E-cig users, 165 exclusive cigarette smokers, and 110 never-users will be enrolled. Tobacco product use will be examined via time-line follow-back use-history measures, real-time measures, and lab measures. Potential participants will be assessed for eligibility via a phone screen. Because biomarker status may be affected by age and sex, groups will be stratified equally for gender (48/52 male/female) and age (≤35/\>35 years).

Brief summary: This study is designed to enhance the understanding of the possible health effects of e-cigarette use by relating the acute and long-term use of e-cigarettes and conventional cigarettes ("products") to well-validated cardiovascular and pulmonary disease biomarkers. Participants will be enrolled in 3 groups: exclusive e-cigarette users, exclusive cigarette smokers, and a control group of never-users. Participants can expect up to 4 weeks of study participation.

Detailed description: E-cigarette use is increasing rapidly in the United States, especially amongst youth, underscoring the vital need to improve understanding of its health risks. Relevant data could inform policy, guide public health and clinical intervention efforts, and inform individuals who might use or who are using this product. This research will significantly enhance the understanding of the possible health effects of e-cigarette use by relating the acute and long-term use of e-cigarettes and conventional cigarettes ("products") to well-validated cardiovascular and pulmonary disease biomarkers. 3 different "use-groups" of participants will be enrolled: exclusive e-cigarette users (n=165), exclusive cigarette smokers (n=165), and a "control" group of never-users (n=110). These groups reflect the primary decisions that people can make regarding their future tobacco use: to continue to smoke cigarettes, to switch to e-cigarettes, or to avoid tobacco use entirely. It is essential that smokers and health care providers have accurate information on the health effect of these choices.

\[Additionally, 100 participants will be invited to be part of an epigenetics sub-study (50 E-cig users, 25 smokers and 25 controls), prior to smoking, an additional 16 ml of blood will be collected in Vacutainer cell separation tubes for peripheral blood monocyte (PBMC) Isolation containing sodium citrate.\]

Product use will be related to well-validated biomarkers that sensitively and reproducibly reflect mechanisms, injury, and/or future risk related to cardiovascular or pulmonary disease. Biomarkers will be related to: 1) acute product use in the laboratory (exposure challenges), 2) lifetime history of product use, and/or 3) real-time measures of product use in participants' daily lives. The primary cardiovascular biomarkers are brachial artery flow-mediated dilation (a measure of endothelial function) and carotid intima-media thickness, a measure of subclinical arterial injury and atherosclerosis. The primary pulmonary disease biomarkers will be measures of lung volumes and flow rates (Forced Expiatory Volume exhaled in the first second (FEV1), Forced vital capacity (FVC), FEV1/FVC) obtained by spirometry. Treadmill exercise stress testing will be performed (to assess aerobic fitness), electrocardiography (to measure heart rate variability, HRV), and measure heart rate, blood pressure, lipids, HgbA1c, and inflammation/oxidation markers (leukocyte count, C-reactive protein, urinary F2 isoprostanes and exhaled nitric oxide). This research will show how product use-groups differ in response to acute product use and long-term use as they are related to key cardiovascular and pulmonary biomarkers. Objective measures of product use include exhaled CO and plasma nicotine/cotinine and urinary nicotine/cotinine concentrations. History of product use within use-groups will be related to biomarker status.

The proposed research will yield vital and comprehensive data regarding product use, subclinical arterial injury, atherosclerosis burden, arterial and pulmonary function, cardiac and aerobic fitness, cardiac autonomic regulation, systemic and pulmonary inflammation, and oxidative stress, as well as other key outcomes. These data will serve as a foundation for future longitudinal investigations of e-cigarette health effects and will inform public policy decisions, clinical intervention, and patient guidance regarding e-cigarettes.

Eligibility criteria: Inclusion Criteria:

* able to read and write English
* no plans to quit smoking and/or e-cig use in the next month
* not using cigars/smokeless/snus tobacco \>/= 1 time per week
* having a stable pattern of current product use
* able to walk at least 2 blocks without assistance or stopping
* Specific to Exclusive Smokers:

  * smokes daily
  * \>/= 5 cigs/day for last 6 months
  * \< 3 uses E-cigs in lifetime
  * \>/= 5 ppm carbon monoxide (CO)
  * Cotinine \> 100 ng/ml
* Specific to Exclusive E-cig users:

  * \</= 2 days per month cigarette use for last 6 months
  * \>/= 5 days per week E-cig use for last 3 months
  * \</= 4 ppm CO
  * Cotinine \> 100 ng/ml
* Specific to Never-users

  * \< 100 cigarettes in a lifetime, none for \> 5 years
  * \< 3 E-cig uses in a lifetime
  * \</= 4 ppm CO
  * Cotinine \< 100 ng/ml

Exclusion Criteria:

* current use of a smoking cessation medication
* women who are pregnant or plan to get pregnant in the coming month
* women who might be pregnant
* incarcerated individuals
* history of sarcoidosis in past 5 years, or active interstitial lung/pulmonary fibrosis
* history of positive Coronavirus-19 test

Primary outcomes:
measure: Brachial Artery Flow-Mediated Dilation (FMD)- Pre Challenge
timeFrame: V2 up to 4 weeks from enrollment visit, fasting
measure: Forced Expiratory Volume (FEV1)- Pre Challenge
timeFrame: V2 up to 4 weeks from enrollment visit , fasting, pre challenge session
measure: Carotid Intima-Media Thickness (IMT)
timeFrame: V2 up to 4 weeks from enrollment visit, only done pre-challenge
measure: Changes in Systolic Blood Pressure Pre- and Post-challenge.
timeFrame: During Visit 2 (1 - 4 weeks post enrollment) before and after smoking/vaping challenge and for controls after a 10 minute break
measure: Changes in Diastolic Blood Pressure Pre- and Post-challenge.
timeFrame: before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
measure: Changes in Heart Rate Pre- and Post-challenge.
timeFrame: Before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
measure: Changes in Brachial Artery Diameter Pre- and Post-challenge
timeFrame: before and after smoking/vaping challenge during Visit 2 (up to 4 weeks from enrollment)
measure: Changes in Brachial Artery Flow Mediated Dilation (FMD) Pre- and Post-challenge
timeFrame: Testing was done after 10 minutes rest and fasting for pre- and post-challenge. The post challenge FMD were recorded 15-20 minuted after end of exposure (up to 4 weeks from enrollment)
measure: Changes in Percent of Sequential Heart Cycles That Differ by More Than 50 ms From Each Other in Length (PNN50, %) Pre- and Post-challenge
timeFrame: During V2 (scheduled up to 4 weeks from enrollment) and obtained after 10 minutes of supine rest, before and after smoking/vaping challenge
measure: Changes in Root Mean Square of Successive Differences Between Normal Heart Beats (RMSSD, ms) Pre- and Post-challenge
timeFrame: heart rate variability recordings of at least 10 minutes per-challenge and 15 minutes post-challenge (up to 4 weeks from enrollment)
measure: Changes in Heart Rate Variability Standing Ratio Pre- and Postchallenge
timeFrame: Ratio was measured pre- and post- smoking/vaping challenge after completion of the 10 minutes of heart rate variability measures (up to 4 weeks from enrollment)
measure: Changes in Predicted Forced Expiatory Volume in 1 Second (FEV1, %) Pre- and Post-challenge
timeFrame: before and after smoking/vaping challenge during Visit 2 (1-4 weeks after enrollment visit)
measure: Changes in Forced Vital Capacity (FVC, %) Pre- and Post-Challenge.
timeFrame: before and after smoking/vaping challenge during Visit 2 Visit 2 which was scheduled 1 to 4 weeks from enrollment visit, fasting
measure: Changes in Ratio Between Predicted Forced Expiatory Volume in First Second and Predicted Total Vital Capacity (FEV1/FVC Ratio) Pre- and Post-challenge
timeFrame: before and after smoking/vaping challenge during Visit 2 (1-4 weeks after enrollment visit)
measure: Changes in Percent Predicted Forced Expiratory Flow at 25 and 75% of the Pulmonary Volume (FEF 25-75, %) Pre and Pos-challenge
timeFrame: Spirometry performed pre-challenge and within 15 minutes post-challenge (up to 4 weeks from enrollment)
measure: Changes in Fractional Exhaled Nitric Oxide (FeNO, Ppb) Pre- and Post-challenge
timeFrame: before and after less than 15 minutes from smoking/ vaping product (up to 4 weeks from enrollment)
Secondary outcomes:
measure: Heart Rate (HR)
timeFrame: Participants attended V2 generally 1-4 weeks after enrollment with a window that allowed up to 4 weeks after enrollment
measure: Heart Rate Variability (HRV) - Pre Product Use Challenge
timeFrame: V2 two was generally scheduled 1-4 weeks after enrollment visit with a window up to 4 weeks. HRV measures obtained after resting supine for 10 minutes
measure: Systolic Blood Pressure (BP)
timeFrame: V2 was up to 4 weeks from enrollment visit, after resting supine for 10 minutes
measure: Forced Vital Capacity (FVC)
timeFrame: recordings obtained during V2 in the morning, fasting and refraining from nicotine for at least 8 hours. This visit was generally 1-2 weeks after enrollment date with a window up to 4 weeks
measure: Fractional Exhaled Nitric Oxide (FeNO)
timeFrame: recordings obtained during V2 in the morning, fasting and refraining from nicotine for at least 8 hours. This visit was generally 1-2 weeks after enrollment date with a window up to 4 weeks
measure: Autonomic Measures - RMSSD
timeFrame: v2 was generally 1-2 weeks after enrollment visit, with a window up to 4 weeks from V1
measure: Arterial Pulse Wave Analysis (PWA), Augmentation Index (at 75 Bpm, %)
timeFrame: v2 was generally 1-2 weeks after enrollment visit, with a window up to 4 weeks from V1
measure: Exercise Treadmill Stress Test (ETT)-Peak METS
timeFrame: Treadmill test done only once at the end of v2 after completion of all other post-challenge assessment tests. V2 was scheduled 1-4 weeks from enrollment vist
measure: Diastolic Blood Pressure (DBP)
timeFrame: V2 was generally 1-2 weeks after enrollment with a window up to 4 weeks from V1, recorded after resting supine for 10 minutes
measure: Peak Rate Pressure Product (RPP, Peak Heart Rate Multiplied by Peak Systolic Blood Pressure)
timeFrame: During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or pretend 10 minute exposure for controls
measure: Heart Rate Reserve (%)
timeFrame: During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or 10 minute pretend exposure for never-users
measure: 60 Seconds Heart Rate Recovery (Beats Per Minute)
timeFrame: During V2 (1-4 weeks after enrollment visit) the treadmill stress test was done last, following Nicotine-containing product challenge (users) or pretend 10 minute exposure for controls
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: James H Stein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tattersall MC, Hughey CM, Piasecki TM, Korcarz CE, Hansen KM, Ott NR, Sandbo N, Fiore MC, Baker TB, Stein JH. Cardiovascular and Pulmonary Responses to Acute Use of Electronic Nicotine Delivery Systems and Combustible Cigarettes in Long-Term Users. Chest. 2023 Sep;164(3):757-769. doi: 10.1016/j.chest.2023.03.047. Epub 2023 Apr 10.