Association of Smoking Cessation With Subsequent Risk of Cardiovascular Disease

Key Points

Question  Among heavy smokers (ie, ≥20 pack-years), what is the association between time since smoking cessation and subsequent risk of cardiovascular disease?

Findings  In this observational cohort study of 8770 participants, former heavy smokers’ risk of cardiovascular disease was significantly lower within 5 years of smoking cessation relative to current smokers (hazard ratio, 0.61) but remained significantly elevated for at least 5 to 10 years and possibly for 25 years after cessation relative to never smokers.

Meaning  Compared with never smokers, former heavy smokers may have significantly elevated cardiovascular disease risk beyond 5 years after cessation.

Importance  The time course of cardiovascular disease (CVD) risk after smoking cessation is unclear. Risk calculators consider former smokers to be at risk for only 5 years.

Objective  To evaluate the association between years since quitting smoking and incident CVD.

Design, Setting, and Participants  Retrospective analysis of prospectively collected data from Framingham Heart Study participants without baseline CVD (original cohort: attending their fourth examination in 1954-1958; offspring cohort: attending their first examination in 1971-1975) who were followed up through December 2015.

Exposures  Time-updated self-reported smoking status, years since quitting, and cumulative pack-years.

Main Outcomes and Measures  Incident CVD (myocardial infarction, stroke, heart failure, or cardiovascular death). Primary analyses included both cohorts (pooled) and were restricted to heavy ever smokers (≥20 pack-years).

Results  The study population included 8770 individuals (original cohort: n = 3805; offspring cohort: n = 4965) with a mean age of 42.2 (SD, 11.8) years and 45% male. There were 5308 ever smokers with a median 17.2 (interquartile range, 7-30) baseline pack-years, including 2371 heavy ever smokers (406 [17%] former and 1965 [83%] current). Over 26.4 median follow-up years, 2435 first CVD events occurred (original cohort: n = 1612 [n = 665 among heavy smokers]; offspring cohort: n = 823 [n = 430 among heavy smokers]). In the pooled cohort, compared with current smoking, quitting within 5 years was associated with significantly lower rates of incident CVD (incidence rates per 1000 person-years: current smoking, 11.56 [95% CI, 10.30-12.98]; quitting within 5 years, 6.94 [95% CI, 5.61-8.59]; difference, −4.51 [95% CI, −5.90 to −2.77]) and lower risk of incident CVD (hazard ratio, 0.61; 95% CI, 0.49-0.76). Compared with never smoking, quitting smoking ceased to be significantly associated with greater CVD risk between 10 and 15 years after cessation in the pooled cohort (incidence rates per 1000 person-years: never smoking, 5.09 [95% CI, 4.52-5.74]; quitting within 10 to <15 years, 6.31 [95% CI, 4.93-8.09]; difference, 1.27 [95% CI, −0.10 to 3.05]; hazard ratio, 1.25 [95% CI, 0.98-1.60]).

Conclusions and Relevance  Among heavy smokers, smoking cessation was associated with significantly lower risk of CVD within 5 years relative to current smokers. However, relative to never smokers, former smokers’ CVD risk remained significantly elevated beyond 5 years after smoking cessation.

Cigarette smoking is a risk factor for cardiovascular disease (CVD) and is responsible for 20% of CVD deaths in the United States^1-6; smoking cessation reduces CVD risk.⁷ However, estimates of the time course of CVD risk reduction among former smokers following cessation have been inconsistent relative to persistent smokers (2-10 years),^8-12 and never smokers (2-20 years).^8-12

Quiz Ref IDSome clinical CVD risk calculators do not distinguish risk between never smokers and former smokers.¹³ The Atherosclerotic CVD (ASCVD) Risk Estimator Plus allows clinicians to identify former smokers but considers their CVD risk identical to never smokers after 5 years.¹⁴ Uncertainty about the time course of CVD risk reduction following smoking cessation could underestimate CVD risk among former smokers, a group increasing as US smoking prevalence declines.¹⁵

Cardiovascular disease risk estimates among former smokers could be improved by frequent, long-term smoking exposure assessment (including status, intensity, abstinence periods, and relapse), objective and time-updated assessment of other CVD risk factors, and continuous CVD incidence surveillance. Data from the Framingham Heart Study (FHS) were analyzed to determine the association between years since smoking cessation and subsequent CVD risk among former smokers relative to persistent smokers and never smokers.

This investigation included FHS original cohort members attending their fourth examination cycle (1954-1958) and FHS offspring cohort participants attending their first examination cycle (1971-1975), when smoking data were first reliably collected. The Boston University Medical Center and Vanderbilt University Medical Center institutional review boards approved the study protocol. All participants provided written informed consent.

There were 4541 original cohort attendees at examination cycle 4 and 5124 offspring cohort attendees at their first examination cycle. The protocol sequentially excluded individuals whose last contact date was equivalent to their baseline date, those with baseline prevalent CVD (self-reported for the offspring cohort; self-reported [before examination 1] and adjudicated [between examinations 1 and 4] for the original cohort), and those with unclear smoking history or missing baseline pack-year information. Participants presented for subsequent examination cycles approximately every 2 years in the original cohort (median, 11 examinations) or 4 years in the offspring cohort (median, 7 examinations).

Methods of quantifying smoking duration and intensity in the FHS have been previously described.¹⁶ Self-reported smoking habits at baseline were used to categorize participants as current, former, or never smokers and to calculate years since quitting for former smokers and pack-years of smoking for ever smokers. Smoking information was updated at subsequent FHS examination cycles to calculate cumulative smoking exposure variables.

Smoking status (current, former, or never) and years since quitting were modeled as time-varying exposures; each participant contributed person-examinations and person-time to the category reflecting smoking status at each assessment. For individuals who developed CVD, the event contributed to the smoking group in which a participant held membership at the time of CVD diagnosis.

To avoid misclassification bias, participants were censored after 1 missed examination plus an additional year without an update (ie, in the original cohort, 5 years without an update, and in the offspring cohort, 9 years without an update).¹⁶ Participants could not reenter the sample after being censored because of uncertainty about smoking patterns during their absence.

Surveillance continued through December 2015 for development of CVD outcomes, including myocardial infarction, stroke, heart failure, and CVD death. For suspected CVD events, medical records were obtained with written patient consent; events were adjudicated by 3 study physicians as previously described.^17-19

Quiz Ref IDCovariates were selected a priori and in part to maximize comparability with prior studies.^8,9,20-22 These included established Framingham CVD risk factors (age, sex, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and total cholesterol)¹³ as well as body mass index (BMI), alcohol consumption, and educational attainment, which may confound the association between smoking and CVD risk.^20-22 Examination decade was included to address temporal trends (eAppendix in the Supplement). We did not include diet and exercise as potential confounders because they were infrequently captured in the original cohort.

Ten complete data sets in each cohort were imputed using multiple imputation by chained equation techniques to account for missingness; predictive mean matching²³ was used for continuous variables and the discriminant function with a noninformative Jeffrey prior²⁴ was used for categorical variables.

Summary statistics were calculated in each cohort separately and combined and stratified by smoking status and intensity. Data from the original and offspring cohorts were analyzed pooled and separately in Poisson regression models to estimate age-, sex-, and education-adjusted incidence rates of first CVD events per 1000 person-years stratified by time-varying smoking status; current and former smokers were categorized as having more than or less than the median of 20 cumulative pack-years (eAppendix in the Supplement).

After confirming that the proportionality assumption was met by assessing interactions with time, Cox proportional hazards regression was used to estimate age-, sex-, and education-adjusted hazard ratios (HRs) for CVD risk comparing former and current smokers with never smokers. An a priori focus on heavier smokers was based on a prior examination of adverse event risk by smoking status in the FHS.¹⁶ In this sample, 71% of CVD events among ever smokers occurred in those with a cumulative smoking history of at least 20 pack-years. Primary analyses focused on these heavy smokers and never smokers in the pooled cohort. Analyses stratified by cohort were considered exploratory.

The time course and magnitude of decreasing CVD risk was analyzed in former heavy smokers vs current heavy smokers in 2 ways using the pooled cohort and original and offspring cohorts separately. First, a categorical variable was created for years since quitting (<5, 5 to <10, 10 to <15, 15 to <25, and ≥25), with current smokers serving as the reference group. Cox proportional hazards regression and Poisson regression were implemented to estimate cause-specific HRs and incidence rates per 1000 person-years, respectively, for CVD risk associated with categorical years since quitting. Second, years since quitting was modeled as a continuous variable (up to 25), assigning current smokers a value of 0. Former smokers with more than 25 years since quitting were assigned a value of 26. In Cox proportional hazards regression, the variable of continuous years since quitting was modeled using restricted cubic splines with 5 knots²⁵ to allow a nonlinear association with the log hazard of CVD, presented graphically.

Analogous methods were used to model the time course and magnitude of lowering CVD risk in former heavy vs never smokers (the reference group in models including categorical years since quitting). In models with continuous years since quitting, never smokers were assigned a value of 50, well above all former smokers. To anchor the HR at years since quitting = 0, a sensitivity analysis explored the influence of including current smokers in the spline comparing former heavy smokers with never smokers.

Cox proportional hazards regression was performed in the pooled cohort (primary analysis) and in the original and offspring cohorts separately (exploratory analyses). A robust sandwich variance estimator was used in all models, and baseline hazards were allowed to differ by cohort in pooled analyses to account for birth cohort effects. Cox and Poisson models were adjusted for all covariates described above. Fourth-order polynomials were placed on age; cubic terms on BMI, total cholesterol, and systolic blood pressure; and quadratic terms on examination decade to allow nonlinear associations between the log hazards of CVD and these continuous predictors. Sensitivity analyses were adjusted for cumulative pack-years when comparing CVD risk among former and current smokers; second-order polynomials were placed on cumulative pack-years. Choice of polynomial terms for continuous covariates is described in the eAppendix in the Supplement. Further sensitivity analyses examined the use of linear terms for continuous predictors instead of polynomial terms. All dynamic variables were updated at each examination and modeled as time-varying covariates. Static variables (sex and education level) remained constant during follow-up.

A sensitivity analysis addressed the influence of observed baseline age differences in the original and offspring cohorts by restricting to offspring person-examinations among participants aged 50 years or older (the mean baseline age of the original cohort) and estimated incidence rates in heavy ever smokers and never smokers by categorical years since quitting. Additional sensitivity analyses included all ever smokers without restriction by pack-years. Other sensitivity analyses included either 2 or 6 smoking data assessments to approximate prior study designs.²⁶

Statistical significance was assessed using a 2-sided P<.05. Statistical analyses used SAS version 9.4. (SAS Institute Inc).

There were 8770 participants (3805 original cohort members and 4965 offspring cohort members) meeting inclusion criteria (Figure 1). In the pooled cohort, the mean age was 42.2 years (SD, 11.8 years), 56% were female, and 75% had at least a high school education (Table 1). Only 2% and 27% of the cohort had baseline diabetes and hypertension, respectively, and median BMI (calculated as weight in kilograms divided by height in meters squared) was in the normal range (median, 24.8; interquartile range, 22.4-27.7), but 78% of the cohort consumed alcohol in the past year (current drinkers), and only 40% of the cohort had never smoked. There were 5308 ever smokers with a median 17.2 (interquartile range, 7-30) baseline pack-years, including 2371 heavy ever smokers (406 [17%] former and 1965 [83%] current). In the original and offspring cohorts, heavy former and current smokers (≥20 pack-years) had similar cumulative pack-year distributions (eFigure in the Supplement) and CVD risk factors (eTables 1 and 2 in the Supplement). The proportion of missing data was low; 89% of offspring cohort person-examinations had complete data. However, in the original cohort, only 51% of person-examinations had complete data because information on alcohol consumption and blood glucose levels was not collected at all examinations.

Of 4115 current smokers at baseline, 1589 (38.6%) quit and never relapsed, while 2117 (51.4%) continued to smoke until they developed CVD or were censored. Most (84.7%) baseline former smokers remained abstinent during follow-up. Among baseline ever smokers, there were 591 smokers who relapsed (ie, began smoking again after reporting abstinence during at least 1 clinic visit). Abstinence periods ranged from 0 to 68 years (median, 3 years; interquartile range, 0-15 years).

During a 26.4-year median follow-up, participants experienced 2435 first CVD events (1612 in the original cohort and 823 in the offspring cohort) (eTable 3 in the Supplement). In both cohorts pooled and separately, current smoking was associated with significantly higher CVD incidence rates per 1000 person-years vs never smoking (Table 2). Incidence rate differences were 4.68 (95% CI, 3.56-5.99) in the pooled cohort, 5.00 (95% CI, 3.17-7.25) in the original cohort, and 4.50 (95% CI, 3.20-6.10) in the offspring cohort. After further categorizing current smokers by pack-years, the association was attenuated in the original cohort with less than 20 cumulative pack-years (incidence rate difference, 0.61; 95% CI, −1.73 to 3.57) but remained significant for current smokers with 20 or more pack-years in the original cohort (incidence rate difference, 6.62; 95% CI, 4.48-9.27) and all current smokers in both the offspring cohort (incidence rate difference among those with <20 pack-years, 3.03 [95% CI, 1.13-5.83] and among those with ≥20 pack-years, 4.92 [95% CI, 3.48-6.68]) and the pooled cohort (incidence rate difference among those with <20 pack-years, 1.65 [95% CI, 0.07-3.62] and among those with ≥20 pack-years, 6.00 [95% CI, 4.61-7.51]) (Table 2). Former heavy smoking in the pooled cohort and offspring cohort was also associated with increased CVD incidence compared with never smoking (pooled cohort incidence rate difference, 1.12 [95% CI, 0.26-2.04]; offspring cohort incidence rate difference, 1.42 [95% CI, 0.68-2.32]) (Table 2).

In adjusted models, smoking cessation was associated with a rapid decline in CVD risk vs continued smoking (Figure 2) such that risk was significantly lower within 5 years of cessation in the pooled cohort (HR, 0.61 [95% CI, 0.49-0.76]; incidence rates per 1000 person-years: current smoking, 11.56 [95% CI, 10.30-12.98]; quitting within 5 years, 6.94 [95% CI, 5.61-8.59]; difference, −4.51 [95% CI, −5.90 to −2.77]) (Table 3). In sensitivity analyses adjusting for cumulative pack-years, results were similar (HR, 0.62 [95% CI, 0.50-0.77]; incidence rate difference, −4.29 [95% CI, −5.64 to −2.59]) (eTable 4 in the Supplement). However, former heavy smoking was associated with higher CVD risk compared with never smoking until 10 to 15 years after cessation in the pooled cohort (HR, 1.25 [95% CI, 0.98-1.60]; incidence rates per 1000 person-years: never smoking, 5.09 [95% CI, 4.52-5.74]; quitting within 10 to <15 years, 6.31 [95% CI, 4.93-8.09]; difference, 1.27 [95% CI, −0.10 to 3.05]) (Table 3). As shown in Figure 2, 16 years after cessation was the point at which the 95% confidence interval for CVD risk among former smokers vs never smokers consistently included the null value of 1. Results remained consistent whether current smokers (ie, years since quitting = 0) were included in the analysis (HR, 1.16 [95% CI, 0.98-1.37]; incidence rate difference, 0.94 [95% CI, −0.12 to 2.17]) (Figure 2A) or not included in the analysis (HR, 1.17 [95% CI, 0.99-1.39]; incidence rate difference, 1.00 [95% CI, −0.06 to 2.29]) (Figure 2B). The time course of CVD risk appeared to differ by cohort (Table 3). In the original cohort, former heavy smoking was no longer significantly associated with increased CVD risk compared with never smoking within 5 to 10 years of cessation (HR, 1.28 [95% CI, 0.97-1.69]; incidence rate difference, 1.88 [95% CI, −0.20 to 4.64]), while in the offspring cohort, this did not occur until at least 25 years after cessation (HR, 1.10 [95% CI, 0.79-1.54]; incidence rate difference, 0.26 [95% CI, −0.54 to 1.39]). Sensitivity analyses with linear terms for continuous covariates instead of polynomial terms were comparable (eTable 5 in the Supplement).

Incidence rates of CVD among current smokers were higher in the original cohort (13.04; 95% CI, 11.21-15.18) than in the offspring cohort (7.71; 95% CI, 6.27-9.48) (Table 3). These differences were substantially attenuated in sensitivity analyses restricted to offspring person-examinations among heavy ever smokers and never smokers aged 50 years or older (incidence rate among current smokers, 11.50; 95% CI, 8.94-14.78) (eTable 6 in the Supplement). In sensitivity analyses including all ever smokers, results comparing CVD risk in former vs current and never smokers were similar (among former smokers quitting <5 years prior vs current smokers: HR, 0.60 [95% CI, 0.50-0.72]; incidence rate difference, −3.92 [95% CI, −4.91 to −2.75]; among former smokers quitting 10-15 years prior vs never smokers: HR, 1.08 [95% CI, 0.88-1.33]; incidence rate difference, 0.38 [95% CI, −0.57 to 1.56]) (eTable 7 in the Supplement). Compared with primary analyses using all available follow-up time points, sensitivity analyses with 6 smoking status assessments produced estimates of similar magnitude but using fewer smoking status assessments produced risk estimates that did not monotonically decrease with years since quitting (eTables 8 and 9 in the Supplement).

Quiz Ref IDThis study found that compared with current heavy smoking, smoking cessation among former heavy smokers was associated with lower CVD risk within 5 years of cessation, reaffirming the cardiovascular benefit of smoking cessation demonstrated by others^8,10-12,27 but also revealing a slow ensuing CVD risk decline over decades (Figure 2). Compared with never smoking, it took 10 to 15 years (pooled cohort) (5 to 10 years in the original cohort and ≥25 years in the offspring cohort) following cessation for former heavy smoking (vs never smoking) to cease being significantly associated with elevated CVD risk.

The upper estimate of this time course is a decade longer than that of the Nurses’ Health Study results for coronary heart disease and cardiovascular death^8,28 and more than 20 years longer than in some prior reports for coronary heart disease^10,11 and stroke.²⁹ Results from the British Regional Heart Study¹² found myocardial infarction risk to persist for more than 20 years after cessation, but findings were limited to men and smoking data were assessed only at baseline. Prior studies primarily examined single CVD components as opposed to composite CVD. In analyses of the full cohort (ie, including those with <20 pack-years), former smoking (vs never smoking) was no longer significantly associated with excess CVD risk within 10 to 15 years of cessation, highlighting the need to stratify by cumulative pack-years. Although the exact amount of time after quitting at which former smokers’ CVD risk ceases to differ significantly from that of never smokers is unknown (and may further depend on cumulative exposure), these findings support a longer time course of risk reduction than was previously thought, yielding implications for CVD risk stratification of former smokers.

Currently, the ASCVD Risk Estimator Plus¹⁴ is used by clinicians to help inform patients regarding their 10-year and lifetime CVD risk and to guide behavior changes to reduce CVD risk. Despite limitations,^30,31 this model is well calibrated in the population for which it was intended³² and, importantly, improves on prior CVD risk calculators^13,33-35 by differentiating risk between former and never smokers. However, the tool considers risk in former smokers to be equivalent to that of never smokers after 5 years since quitting. Thus, as the proportion of former smokers in the United States increases with more current smokers quitting, so does the potential to underestimate CVD risk using current tools, especially among heavier smokers. The present investigation does not support the assumption that former smokers achieve the same CVD risk as never smokers within 5 years of quitting. Future studies should investigate the extent to which including comprehensive data on smoking exposure, such as pack-years smoked and years since quitting, would improve the performance of existing CVD risk prediction tools and, by extension, CVD health outcomes.

In Figure 2A, CVD risk appeared to increase at about 10 years after cessation among former heavy smokers, but only when current smokers were included in the analysis. However, 95% confidence bands include a smooth decline in risk without this artifactual increase, as evidenced by the smooth curve when current smokers are not included (Figure 2B).

Quiz Ref IDA strength of the present analysis is the rich data source including 2 distinct but similar cohorts with a median follow-up of more than 26 years. The FHS features frequent, repeated, in-person assessments of smoking status and intensity over the course of half a century or more, allowing for comprehensive lifetime capture of smoking. In addition, the FHS simultaneously collected data on CVD risk factors, which allows robust adjustment for confounders. Continuous participant follow-up for CVD incidence also allows for accurate and near-complete event capture. This investigation extends prior knowledge by using a self-reported smoking ascertainment method, including prospectively gathered and regularly time-updated data on smoking status and intensity collected during in-person visits. Sensitivity analyses with fewer smoking status assessments led to inconsistent results in which relative risk among former smokers did not decrease in a monotonic fashion with increasing years since quitting.

In lifetime analyses, people develop comorbidities with increasing age, which could influence smoking cessation patterns. To minimize this potential bias from unmeasured confounding, analyses accounted for baseline differences between cohorts (eg, age), differences among current, former, and never smokers, temporal trends (eg, declining smoking rate, increasing BMI), birth cohort effects, and factors that could influence both smoking cessation and CVD risk, including sociodemographic factors and known CVD risk factors, which were time-updated. Thus, the effect of unmeasured confounding on the overall findings is likely modest.

Quiz Ref IDThis study also has several limitations. First, compared with some prior studies,²⁶ the sample size was smaller, but it was large enough to address the questions of interest and also provided thoroughly captured longitudinal smoking data. The limited sample size also precluded analyses yielding CVD risk estimates among subcategories of lighter smokers (<20 lifetime pack-years); thus, the primary findings are applicable to ever smokers with a cumulative smoking history of at least 20 pack-years. Second, information on environmental tobacco smoke exposure and use of other types of tobacco was not available for most participants and was not included. Third, as with other investigations using data from the FHS original and offspring cohorts, this investigation is composed primarily of white individuals of European ancestry, potentially limiting generalizability of results to individuals of other races/ethnicities.

Among heavy smokers, smoking cessation was associated with significantly lower CVD risk within 5 years relative to current smokers. However, relative to never smokers, former smokers’ risk remained significantly elevated beyond 5 years after smoking cessation.

Corresponding Author: Meredith S. Duncan, MA, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Ste 300-A, Nashville, TN 37203 (meredith.s.duncan@vumc.org).

Author Contributions: Ms Duncan and Dr Tindle had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Duncan, Freiberg, Greevy, Vasan, Tindle.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Duncan, Freiberg, Vasan, Tindle.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Duncan, Freiberg, Greevy, Kundu.

Obtained funding: Vasan, Tindle.

Administrative, technical, or material support: Vasan, Tindle.

Supervision: Freiberg, Greevy, Vasan, Tindle.

Conflict of Interest Disclosures: Dr Tindle reported providing input on design for a phase 3 trial of cytisine proposed by Achieve Life Sciences and being a principal investigator of National Institutes of Health–sponsored studies for smoking cessation that include medications donated by the manufacturers. No other disclosures were reported.

Funding/Support: Dr Freiberg is supported by the Dorothy and Laurence Grossman Chair in Cardiology. Dr Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Dr Tindle is supported by the William Anderson Spickard Jr Chair in Medicine and the National Cancer Institute Moonshot Initiative (grant 3P30CA068485-22S3). The FHS received the support of contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the National Heart, Lung, and Blood Institute for this research.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Additional Contributions: We acknowledge the dedication of the FHS study participants and staff, without whom this research would not be possible.