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Improved aerobic capacity in a randomized controlled trial of noncombustible nicotine and tobacco products

01 June 2025



Abstract

Smoking negatively impacts aerobic capacity, primarily by reducing V̇O2max, the gold standard measure of cardiorespiratory fitness. While smoking cessation is known to improve vascular function, exercise performance, and oxygen uptake, its specific impact on V̇O2max remains underexplored. Specifically, no research has yet evaluated V̇O2max changes following a switch to electronic cigarettes (ECs) or heated tobacco products (HTPs). This is a secondary analysis of the CEASEFIRE trial, a 12-weeks randomized controlled switching trial comparing the impact of ECs or HTPs on changes in smoking behaviour. The trial offers a unique opportunity to prospectively examine the relationship between smoking behavior and aerobic capacity, and to examine—for the first time—the specific impact of exclusive EC or HTP use on V̇O2max. Changes in VO₂max were analized across three smoking phenotypes: continuous smokers, those who reduced smoking, and those who abstained from smoking Additionally, VO2max was also evaluated specifically in participants who completely abstained from smoking tobacco cigarettes, evaluating outcomes in exclusive EC and HTP users. Quitters showed the greatest improvement in VO2max at both week 4 (2.4 ± 1.7 mL kg−1 min−1) and week 12 (2.7 ± 1.9 mL kg−1 min−1). Reducers also exhibited significant VO2max increases (1.3 ± 1.9 mL kg−1 min−1 at week 4: 1.9 ± 1.8 mL kg−1 min−1 at week 12), while Failures (i.e. those who continued smoking) showed no change. Exclusive use of EC and HTP resulted in statistically significant and clinically relevant improvements in V̇O2max. Compared to baseline, V̇O2max significantly increased at week 4 (EC: 38.4 ± 5.9 to 41.0 ± 6.1 mL kg−1 min−1; HTP: 39.2 ± 6.7 to 41.4 ± 6.4 mL kg−1 min−1, both p  < 0.0001) and week 12 (EC: 38.4 ± 5.9 to 41.4 ± 6.3; HTP: 39.2 ± 6.7 to 41.6 ± 6.5 mL kg−1 min−1, both p < 0.0001). No significant differences between EC and HTP were observed at either time point. Rapid improvements in V̇O2max can happen when healthy smokers switch to exclusive use of ECs or HTPs. These findings reinforce the potential cardiorespiratory benefits of smoking cessation and harm reduction strategies.

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Introduction

Chronic exposure to the harmful chemicals in tobacco cigarette smoke significantly impairs physical fitness, primarily by reducing oxygen availability at the tissue level and diminishing both aerobic and anaerobic exercise capacity1,2.

Smoking is well-documented to decrease endurance performance in healthy individuals and negatively impacts physical fitness test outcomes, with reduced oxygen uptake capacity playing a central role3,4. Furthermore, an inverse relationship has been observed between smoking history and maximal aerobic capacity (V̇O2max)2,5, the gold standard for assessing cardiorespiratory fitness6.

V̇O2max represents the maximum rate of oxygen consumption measured during incremental exercise and reflects the efficiency of the respiratory, cardiovascular, musculoskeletal, and metabolic systems in oxygen transport and utilization. A higher V̇O2max indicates improved aerobic capacity, which is associated with better cardiorespiratory fitness and reduced cardiovascular and all-cause mortality risk7,8.

Importantly, the negative effects of smoking on cardiorespiratory performance can be reversed upon cessation. Studies have shown that smoking cessation leads to significant improvements in vascular endothelial function, exercise performance and cardiovascular responses to physical activity9,10,11,12. These benefits can be observed as early as 12 weeks post-cessation and persist for up to three years9,10,11,12. Notably, the rapid improvements in V̇O2max observed post cessation suggest that this parameter may serve as a sensitive biomarker of physiological recovery, reflecting early changes in cardiorespiratory health. This makes V̇O2max particularly valuable in the context of smoking cessation and switching trials involving alternative nicotine and tobacco products. However, the physiological effects and health benefits of smoking cessation—especially those measured by V̇O2max—remain underexplored, with only one study to date having rigorously assessed this outcome11. Moreover, no research has yet evaluated V̇O2max changes following a switch to electronic cigarettes (ECs) or heated tobacco products (HTPs), representing a critical gap in the literature.

ECs and HTPs, battery-powered devices that deliver nicotine without combustion, have gained popularity as alternatives to conventional cigarettes13,14. These products are widely used by smokers aiming to reduce their exposure to harmful chemical emissions from combustion15,16,17. The key to their reduced harm potential lies in the elimination of combustion18, which is the primary source of toxicants in cigarette smoke. Although HTPs contain tobacco and may not offer the same level of harm reduction as ECs, both products have been explored for their potential to lower smoking-related harm19,20 and their effectiveness as smoking cessation aids remains subject to ongoing research21,22.

We hypothesize that smokers who transition from combustible tobacco cigarettes to non-combustible nicotine/tobacco products (N–C NTPs) such as ECs and HTPs may experience measurable improvements in cardiorespiratory performance as a result of eliminating tobacco smoke exposure23. While previous research has documented the physiological effects and health improvements associated with switching to these products24,25,26 the specific impact on V̇O2max remains insufficiently explored. Given that V̇O2max is a well-established indicator of aerobic capacity, any observed improvements following smoking cessation could provide valuable insights into the potential respiratory and cardiovascular benefits of smoking substitution.

This study examines changes in V̇O2max, measured using the sub-maximal Chester Step Test, in relation to smoking reduction and smoking abstinence among participants in the CEASEFIRE trial27. CEASEFIRE is a large prospective randomized controlled trial designed to assess smoking reduction and cessation rates among adult smokers transitioning from conventional cigarettes to N–C NTPs (ECs and HTPs). V̇O2max was assessed at baseline and monitored at multiple follow-up visits.

The CEASEFIRE trial offers a unique opportunity to prospectively investigate the impact of smoking reduction or cessation on aerobic capacity. This study presents a secondary analysis of the trial data, specifically examining changes in V̇O2max across three groups: continuous smokers, those who reduced smoking, and those who abstained from smoking. Additionally, no research has ever documented V̇O2max changes after switching to ECs or HTPs. Therefore, we conducted a separate analysis to assess the differential impact of exclusive EC use versus exclusive HTP use on V̇O2max, offering unique insights into the effects of these non-combustible nicotine and tobacco products.

Methods

The current study serves as a secondary analysis of a large prospective randomized control non-inferiority trial that focused on examining the quit and reduction rates among adult smokers who transitioned from conventional tobacco cigarettes to non-combustible nicotine/tobacco products (N–C NTP) namely HTPs and ECs. The specifics regarding the population sample, study design, Ethics Review Board approval, study registration, and CONSORT reporting standards were previously detailed28.

Research was performed in accordance with the relevant guidelines/regulations and according to the Declaration of Helsinki. Informed consent was obtained from all participants and/or their legal guardians.

The de-identified datasets from the trial were sourced from the open science repository maintained by the Center of Excellence for the Acceleration of Harm Reduction (CoEHAR) at the University of Catania, and subsequently utilized for this analysis: https://zenodo.org/records/7941030

Since the study exclusively used publicly available, de-identified data, it was exempt from ERB review. Only complete and reliable data were extracted to ensure analytical integrity.

Study participants

Adult smokers of ≥ 10 cigarettes per day (regularly smoking for at least the past year) and with exhaled carbon monoxide (eCO) levels of ≥ 7 ppm, not planning to quit soon (within the next 30 days from screening), but open to switching to HTPs or ECs were recruited from hospital and university staff, via social media, and through word of mouth. They confirmed no quit intention by answering “No” to these two questions: “Do you plan to quit smoking within the next 30 days?” and “Do you wish to participate in a smoking cessation program?”. They also met specific exclusion criteria including: (1) history of mental disease, (2) history of alcoholism or drug abuse, (3) presence of clinical diseases that, in the opinion of the investigator, would jeopardize the safety of the participant or impact the validity of the study results, (4) use of any N–C NTPs within the last 3 months, and (5) use of nicotine replacement therapy or other smoking cessation therapies within the last 3 months. Subjects were informed that the purpose of the study was to quantify the impact of reductions in cigarette consumption on cardio-respiratory performance. The study was approved by the local Ethical Review Board (Comitato Etico, Azienda Ospedaliero Universitaria “Policlinico-V. Emanuele,” Università di Catania, Italy; approval no. 215/2017/PO). All participants provided written informed consent prior to participation in the study. The study was registered at ClinicalTrial.gov (trial registration ID: NCT03569748).

Trial design and study visits

Eligible subjects were enrolled into a 12-week, randomized, two parallel arm, controlled trial consisting of seven study visits (one screening visit and six study visits) at smoking cessation clinics of the University of Catania (Centro per la Prevenzione e Cura del Tabagismo – CPCT) designed to compare cessation and reduction rates between HTPs and ECs study arms. The trial also measured maximal aerobic capacity by Chester step test at baseline, week-4, and week-12.

At the baseline visit, subjects were randomized to either the HTP (IQOS 2.4) group or the EC (JustFog Q16 Starter Kit) group and were instructed to use the assigned product to assist in abstaining from cigarette smoking. Participants were asked to return to the CPCT for follow-up visits to obtain regular supplies of tobacco sticks (for IQOS 2.4 users) and e-liquid refills (for JustFog Q16 users). During these visits, subjects were required to report their tobacco cigarette and EC/HTP consumption, undergo measurements of eCO levels, and have their blood pressure (BP) and heart rate (HR) assessed. Self-reported use of tobacco cigarette and HTPs or ECs since the previous visit was noted in a study diary and recorded in the electronic case report form at each visit (from V2 to V6). Additionally, EC/HTP consumption was verified through checks of product use (by counting the number of used and unused tobacco sticks and liquid refill containers) and calculated as average consumption on a per daily basis. Additionally, the Chester step test was scheduled to be repeated at weeks 4 and 12.

Exhaled carbon monoxide measurements

Measurements of exhaled carbon monoxide (eCO) levels, expressed in parts per million (ppm), were taken using a hand-held CO meter (Micro CO; Micro Medical Ltd, UK). Subjects were instructed to exhale slowly into a disposable mouthpiece connected to the CO meter, following the manufacturer’s recommendations. Expiratory maneuvers were taken late in the morning or early in the afternoon with participants sitting comfortably. Participants were requested to refrain from smoking, vaping, or using heated tobacco products (HTPs) for at least 30 min prior to each measurement. Smoking status was objectively confirmed when eCO levels exceeded 10 ppm.

Chester step test procedure

The Chester Step Test (CST) is a validated test assessing maximal aerobic capacity (maximal oxygen consumption, V̇O2Max) by having subjects step on and off a gym step at gradually increasing stepping rates every two minutes to increase their heart’s rate, which was used to calculate their V̇O2 max29,30. The test provides good test–retest reliability and is an acceptable method for estimating V̇O2max in the general healthy adult population31.

Before the commencing the test, participant’s blood pressure (BP) and resting heart rate (HR) were measured. Participants were then instructed to step in time with the beat of a metronome initially set at 15 beats/minute. Every 2-min, stepping rate was increased by 5 steps/minute (from 15 to 35 bpm, a total of 5 stages). HR and rating of perceived exertion (RPE) were recorded at each stage. The test continues until the participant reaches a specific HR (80% HR max) or a moderately vigorous level of exertion (RPE below 14). Aerobic capacity (V̇O2Max) and fitness rating are determined using a Chester Step Test calculator available at: https://www.brianmac.co.uk/chester.htm.

Smoking phenotypes

The study analyzed the time-course of V̇O2max changes in relation to three different smoking phenotypes: quitters vs. reducers vs. failures.

Smoking abstinence is defined as complete self-reported abstinence from cigarette smoking since the previous study visit, which was biochemically verified by eCO levels of < 10 ppm. Smokers in this category are classified as quitters. Continuous abstinence rate from week 2 to week 4 (CAR 2–4 Weeks) and from week 2 to week 12 (CAR 2–12 Weeks) were used as a robust characterization of smoking abstinence. Among the quitters, we employed a further subclassification to distinguish between individuals who achieved abstinence after switching to ECs and those who quit after switching to HTPs. This allowed for a more granular comparison of outcomes based on the type of study product used.

Smoking reduction is defined as self-reported ≥ 50% reduction in the number of cigarettes smoked per day from baseline (eCO levels were measured to verify smoking status and confirm a reduction compared with baseline). Smokers in this category are classified as reducers. Continuous reduction rates from week 2 to week 4 (CRR 2–4 Weeks) and from week 2 to week 12 (CRR 2–12 Weeks) were used as a robust characterization of smoking reduction.

Smoking failure is the smoking phenotype that excludes smoking abstinence or smoking reduction. Smokers in this category are classified as failures.

Statistical analysis

In the primary analysis, a total of 220 smokers were enrolled, with 110 participants assigned to the EC Study arm and 110 to the HTP Study arm. For the current secondary analysis, subjects’ V̇O2max measurements from both study arms were pooled and evaluated for changes from baseline at the 4-week and 12-week time points, stratified by smoking behavior phenotype: Failures (continued smokers), Reducers, and Quitters (complete abstainers). In addition, this secondary analysis also investigated possible differential impact of exclusive EC use and exclusive HTP use on V̇O2max, providing novel insights into the cardiorespiratory effects of N–C NTPs.

Categorical variables were summarized using counts and percentages, while continuous variables with symmetrical distribution were presented as mean and standard deviations (SD). Skewed continuous data were summarized using median and interquartile ranges (IQR). Comparisons were conducted using the χ2 test for categorical variables, and one-way Analysis of Variance (ANOVA) and Kruskal–Wallis tests for normally and not normally distributed data, respectively. A two-way ANOVA was used to assess the effects of classification and sex on V̇O2 max at baseline. A repeated measures ANOVA model was applied to examine potential effects of classifications and sex on V̇O2 max over time. To evaluate the association between smoking phenotypes and changes in V̇O2 max from baseline to week 4 and week 12, while accounting for potential confounders, a multiple linear regression analysis was performed. The outcome variable was ΔV̇O2 max (i.e., the absolute difference in V̇O2 max from baseline to weeks 4 and 12), with classification, age, sex and BMI changes from baseline included as independent factors. These variables were selected based on existing evidence indicating their potential influence on cardiorespiratory performance.

The analyses were performed using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL) for Windows version 20.0 and p values < 0.05 were considered significant.

Results

For this secondary analysis, data from 187 subjects were available. This accounted for missing data from subjects who either could not perform the Chester Step Test or did not qualify as continuous smoking phenotypes (Quitters, Reducers, or Failures, based on the provided definitions). Among the 187 evaluated subjects, 32 (17%) were classified as Failures, 88 (47%) as Reducers, and 67 (36%) as Quitters. A description of the evaluated sample is presented in Table 1. Table 2 illustrates the level of cigarette consumption for each smoking phenotype, showing that Reducers had on average a greater than 75% reduction in cigarette consumption from baseline.


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