Tobacco Harm Reduction
Are Heated Tobacco Products a Pragmatic Middle Ground for Recalcitrant Smokers? – Revisiting the Problem in the Context of the Current Pandemic
Rafael R. Castillo1,*, Marie A. Barrientos-Regala1,2, Ma. Joan Dymphna Reaño1,2, Reginald Arimado2
1Manila Doctors Hospital, Manila, Philippines
2Cardio-Metabolic Research Unit (CaMeRU), FAME Leaders Academy, Makati City, Philippines
Received: 21 October 2021; Accepted: 05 November 2021; Published: 09 November 2021
Citation: Rafael R. Castillo, Marie A. Barrientos-Regala, Ma. Joan Dymphna Reaño, Reginald Arimado. Are Heated Tobacco Products a Pragmatic Middle Ground for Recalcitrant Smokers? – Revisiting the Problem in the Context of the Current Pandemic. Cardiology and Cardiovascular Medicine 5 (2021): 566-571.
Recalcitrant smokers managed for their cardiovascular problems pose a serious challenge to practicing physicians in their efforts to effectively reduce cardiovascular and overall health risk in these patients. This problem has been magnified during the current pandemic, when the already increased health risk of active smokers is aggravated further in the event that they develop coronavirus disease 2019 (COVID-19). Active smoking increases the risk of developing severe COVID-19 by around two folds, and those with chronic obstructive pulmonary disease (COPD)—which many recalcitrant smokers are likely to have already—have a fourfold increase in risk translating to much poorer clinical outcomes. This is aggravated by the delay in diagnosis since the symptomatology in COPD with acute exacerbation and COVID-19 may significantly overlap.
This predicament with recalcitrant smokers during this pandemic has prompted us to reconsider our previous policy to give up on them after six months of making them quit smoking totally. The current pandemic highlighted the need to explore alternatives that could at least mitigate the cardiovascular and COVID-19 risk of recalcitrant smokers. Based on the potential to reduce health risk and also on patient feedback, we have allowed the use of heated tobacco products (HTPs) in our recalcitrant smokers who really could not attain total smoking cessation despite all known smoking cessation measures. Quite different from electronic cigarettes, HTPs produce aerosols, still containing nicotine, using a battery-powered heating system device. Based on studies, the amount of toxic substances a smoker gets is up to 95 percent less, compared to traditional tobacco smoking. Though HTPs may be considered a pragmatic middle ground for recalcitrant smokers, there is still some degree of addiction; hence, legislative and regulatory control measures are imperative, so as to prevent the youth and nonsmokers to be “seduced” into trying them. However, these regulatory measures should not be more stringent than what are currently imposed on tobacco smoking since it would defeat the purpose of getting current smokers out of this deadly vice.
Keywords: Recalcitrant smokers, COVID-19, heated tobacco products, cardiovascular risk reduction
A major challenge in clinical practice is dealing with heart patients who may be classified as recalcitrant smokers, defined as those who have an obstinately uncooperative attitude towards smoking cessation. They may show initial efforts of following the smoking-cessation programs we implement in our clinics, but there is an utter lack of perseverance and will to persist until the end goal of complete smoking cessation is achieved.
The doctors in our clinics have tried all known measures of convincing these recalcitrant smokers; i.e., by persuasion, motivation, even combining them with threats on the health hazards they are likely to develop if they do not stop smoking. At best, we are only successful in around three out of 10 cases.
More frequently, we reach exasperation point with recalcitrant smokers, and we have decided to implement a policy that if they do not quit smoking in six months, we advise them to go to another clinic for their subsequent follow-up, as we consider ourselves a failure in effectively addressing a major risk factor that they have.
It is always a happy occasion when a few of these “expelled” patients eventually succeed in quitting smoking, and we gladly welcome them back, should they wish to be under our continuing medical care. However, these small victories are dampened when a few, who have already licked the vice previously, slide back and return to smoking. Realizing the stern policy on recalcitrant smokers we adhere to and the six-month grace period for smoking cessation they are allowed, they voluntarily go to other clinics for their follow-up monitoring and management. Some of these recalcitrant smokers decide not to follow up with any doctor at all, and they just maintain the initial drugs they are prescribed, until they develop complications, for which they are rushed to the emergency room.
This stern carrot-and-stick approach towards our smoker-patients has been the standard policy in our practice until the start of the pandemic last year, when we realized we might have been too harsh on our recalcitrant smoker-patients. The pandemic has made us rethink our policy, and explore other means of assisting those who simply could not give up their nicotine addiction.
- Smoking and COVID-19 Severity
Smoking and coronavirus disease-2019 (COVID-19) definitely make a killer combination leading to a complicated clinical course and worse outcomes. Majority of our recalcitrant smokers have smoking histories of more than 20 pack years, and already have mild to moderate chronic obstructive pulmonary disease (COPD), which is a major risk factor for developing severe COVID-19 .
In a pooled meta-analysis of seven separate studies comprising a total of 1,726 patients, a statistically significant association between smoking and severity of COVID-19 outcomes was shown. This meta-analysis, which included studies on COVID-19 from December 2019 to 22 March 2020, showed that pre-existing COPD was associated with a four-fold increased risk of developing severe COVID-19. The same study also indicated that active smoking increases the risk of developing severe COVID-19 by around two folds .
The presence of COPD in our recalcitrant smoking patients raised some clinical challenges since the clinical presentation of COVID-19 may be difficult to distinguish from the symptomatology of acute exacerbation of COPD. Many of these recalcitrant smokers may already have recurrent productive cough. This dilemma in differentiating if it is COPD with acute exacerbation or COVID-19 may cause delayed treatment and appropriate medical intervention, and a worse clinical outcome [1, 2].
Active smoking, even in the absence of COPD, may also increase the risk of recalcitrant smokers for severe COVID-19. Reddy et al. analyzed 47 studies enrolling 32,849 symptomatic and hospitalized COVID-19 patients, with 8,417 (25.6%) in this large pool of patients reporting a smoking history. There is an increased propensity for patients with any smoking history to develop severe COVID-19 and worse in-hospital outcomes. In the group who were active or current smokers, the risk was highest, with an increased risk of severe COVID-9 (risk ratios [RR]: 1.80; 95% confidence interval [CI]: 1.14-2.85; P = .012), and severe or critical COVID-19 (RR: 1.98; CI: 1.16-3.38; P = .012) .
So, this current COVID-19 pandemic is really one of the most adverse developments for recalcitrant smokers. From time to time, we hear of a former patient whom we had “expelled” from the clinic admitted to the intensive care unit for critical COVID-19, intubated for mechanical ventilation, and eventually succumbing to it. Some patients may be fortunate to survive, but only after a stormy clinical course in the hospital for pulmonary or cardiac complications like acute coronary syndrome or congestive heart failure .
We could not help but wonder if those who had died could have remained alive if we continued to monitor and follow them up in our clinic .
- Exploring less Harmful Smoking Alternatives
So, since last year, we eased up on our strict policy on recalcitrant smokers, and made a firm resolve to double our efforts to get them to quit smoking. The threat of more severe COVID-19 if they continued to smoke has increased our success rate to around 50 percent. It’s quite perplexing, though, that half of our smoker-patients still keep smoking. However, most smokers are simply helpless against their nicotine addiction; and the nicotine dependence has led to a pattern of heavy smoking despite its known health hazards, which is resistant to change [4, 5].
Our main goal is still to make them quit permanently. However, from a non-negotiable policy, we have decided to shift to whatever pragmatic middle-ground we could find for recalcitrant smokers; since at least half of these smokers, or more than half in the pre-COVID era, simply could not quit.
In our cardiovascular clinics, we are still trying to look for the best middle ground, and still hoping that eventually, we could push them up further to the real safe, high ground of having beaten their addiction completely and permanently .
When we explored the possible alternative options, we looked at the studies on vaping or electronic cigarettes (e-cigs), but opted not to consider it since the reports on e-cig- or vaping-product-use-associated lung injury (EVALI) were too much of a concern to ignore. More than 60 deaths and 2,750 hospitalizations due to EVALI have so far been reported .
A patient told us about heated tobacco products (HTPs), so we also started reviewing the published data on it. HTPs produce aerosols containing nicotine and other chemicals, which are inhaled by users through the mouth, like the conventional cigarette, but the stick is not lit; it’s just heated using a battery-powered heating system device. The inhaled substance still contains nicotine (from the heated tobacco), which makes it still addictive and concerns have been raised on attracting adolescents and the youth, as well as nonsmokers . Based on some studies, the amount of toxic substances a smoker gets is up to 95 percent less, compared to traditional tobacco smoking .
There are also short-term studies suggesting it could reduce the inflammatory biomarkers produced by conventional cigarette smoking . Any significant inflammation in the body is expected to lead to adverse consequences, and reducing it could possibly mitigate these adverse complications, although this has to be still proven with HTPs .
Furthermore, there have also been studies on HTPs showing its less impactful effects compared to conventional cigarette smoking on the outcomes of oxidative stress, platelet activation and blood pressure [10, 11].
An unpublished meta-analysis conducted by our group on the effects of HTPs vs traditional tobacco cigarettes (TTCs) on predictors of cardiovascular risk among adult smokers showed a significant reduction in heart rate, and significant increases in flow mediated dilatation and high density lipoprotein cholesterol level in the HTP compared to the TTC groups. There were no statistically significant differences in systolic and diastolic blood pressures, serum low density lipoprotein cholesterol, triglycerides, total cholesterol and pulse wave velocity .
Though these studies contribute to our growing knowledge on HTPs and its possible less detrimental impacts on health, larger studies with long term follow-up are still required to corroborate these results.
Hence, based on these preliminary information on less harmful effects of HTPs compared to cigarette smoking, we have allowed our recalcitrant smoker-patients to shift to this alternative, but always reminding them that quitting smoking is the ultimate goal. We hope to be able to provide data later on, if these less harmful mechanistic effects of HTPs could really translate to long-term beneficial outcomes. The jury is still out on its long-term benefit or harm. From where we stand now, HTPs appear to be a relatively less harmful middle ground than traditional smoking. Even treatment guidelines recognize the equipoise, and encourage being on the side of caution, since there is still “insufficient data” to either recommend or advise against HTPs. According to the World Health Organization (WHO), there is no available evidence to conclude whether HTP use is associated with any long-term clinical outcome—positive or negative—from exposure to the mainstream or secondhand emission .
In 2019 statement, the WHO said that the available evidence demonstrates that exposure to harmful and potentially harmful chemicals from HTPs may be lower relative to cigarettes .
The American Heart Association also issued a policy statement on tobacco smoking alternatives and cited epidemiological studies on smokeless tobacco use coming from Scandinavia, where a large percentage of men use snus, a smokeless tobacco product that contains nicotine, but has relatively low levels of carcinogens and other toxins .
With current data, it looks evident that HTPs are likely less harmful than traditional smoking, but are still more harmful than not smoking. This has to be thoroughly discussed with an open mind by not only the medical or scientific community, but the legislators and regulators as well. After all, the lives of tens of millions of recalcitrant smokers may depend on the options we offer them if they really cannot quit smoking .
Smokers may be rightfully considered as victims of an addictive disease, and those who cannot quit remain part of the health equation of every nation, just as much as the healthy nonsmokers. They actually need more understanding, more attention, and more care from their physicians, who should aim for a treatment goal of at least partially protecting them from the cardiovascular and other health hazards of cigarette addiction.
This has to be balanced by the downside of HTPs—that the youth and nonsmokers might be “seduced” into trying them. It cannot be overemphasized that regardless of whether they are heated by flame or electronically, HTPs still contain nicotine, which is highly addictive. This is where legislation and regulation come in. It is essential to have a strict but balanced regulation. However, it should not be more restrictive than currently enforced regulation for cigarettes. Strict control measures must be put in place to prohibit sales of HTPs to nonsmokers and the youth. On the other hand, current smokers must be given the free choice to shift to it, if they wish to, and especially with the guidance of their physician. Though HTPs are smoke-free, they should still not be allowed in public. Although the harmful particulate pollution they cause is relatively less compared to passive cigarette smoking, the potential harm to secondhand smoke could not be completely discounted .
The science on HTPs and other smoking alternatives is still evolving. More data are definitely needed to draw definitive conclusions on its benefit or exact harm. The current pandemic has pushed clinicians to a corner to come up with an immediate palliative alternative to mitigate the potential risk of recalcitrant smokers should they catch the dreaded virus. With the present level of scientific information known about HTP, it appears to be a pragmatic alternative and middle ground to recalcitrant smokers in the context of the current pandemic.
- Zhao Q, Meng M, Kumar R, et al. The impact of COPD and smoking history on the severity of COVID-19: A systemic review and meta-analysis. J Med Virol 92 (2020): 1915-1921.
- Reddy R, Charles W, Sklavounos A, et al. The effect of smoking on COVID-19 severity: A systematic review and meta-analysis J Med Virol 93 (2021): 1045-1056.
- Castillo R, Medical Files: Are heated tobacco products the safer choice? May 25, (2021).
- Fagerström, Karl-Olov. Measuring Degree of Physical Dependence to Tobacco Smoking with Reference to Individualization of Treatment. Addictive Behavior 3 (1978): 235-241.
- Pormerieau OF, Fertig JB, Shanahan SO. Nicotine dependence in cigarette smoking: an empirically-based, multivariate model. Pharmacol Biochem Behav 2 (1983): 291-9.
- Centers for Disease Control and Prevention. Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping, Products (2021).
- Centers for Disease Control and Prevention. Heated Tobacco Products: What’s the Bottom Line? (2021).
- Znyk M, Jurewicz J, Kaleta D. Exposure to Heated Tobacco Products and Adverse Health Effects, a Systematic Review. International Journal of Environmental Research and Public Health 18 (2021): 6651.
- Ogden MW, Marano KM, Jones, et al. Switching from usual brand cigarettes to a tobacco-heating cigarette or snus: Part 3. Biomarkers of biological effect. Biomarkers 20 (2015): 404–410.
- Biondi‐Zoccai G, Sciarretta S, Bullen C, Nocella C, Violi F, Loffredo L, … Frati G. Acute Effects of Heat‐Not‐Burn, Electronic Vaping, and Traditional Tobacco Combustion Cigarettes: The Sapienza University of Rome‐Vascular Assessment of Proatherosclerotic Effects of Smoking (SUR‐VAPES) 2 Randomized Trial. Journal of the American Heart Association 8 (2019).
- Ikonomidis I, Vlastos D, Kostelli G, et al. Differential effects of heat-not-burn and conventional cigarettes on coronary flow, myocardial and vascular function. Sci Rep 11 (2021): 11808.
- Barrientos-Regala M, Reaño JD, Arimado R, Castillo RR. A Systematic Review and Meta-Analysis on the Effects of Heated Tobacco Products vs Traditional Tobacco Cigarettes on Heart Rate, Blood Pressure and Other Predictors of Cardiovascular Risk Among Adult Smokers (unpublished).
- World Health Organization. Heated Tobacco Products a Brief; World Health Organization Regional Office for Europe: Copenhagen, Denmark (2020).
- Piano MR, Benowitz NL, FitzGerald GA, Corbridge S, Heath J, Hahn E, Pechacek TF, Howard G. Impact of Smokeless Tobacco Products on Cardiovascular Disease: Implications for Policy, Prevention, and Treatment: A Policy Statement From the American Heart Association Circulation 122 (2010): 1520–1544.
A Systematic Review and Meta-Analysis on the Effects of Heated Tobacco Products vs Traditional Tobacco Cigarettes on Heart Rate, Blood Pressure and Other Predictors of Cardiovascular Risk Among Adult Smokers
Marie Barrientos-Regala, M.D.1,2, Joan Dymphna P. Reaño, M.D.1,2, Reginald P. Arimado1, Rafael R. Castillo, M.D.1,2
1 CardioMetabolic Research Unit (CaMeRU), FAME Leaders Academy, Makati City, Philippines
2 Section of Adult Cardiology, Department of Internal Medicine, Manila Doctors Hospital, Manila, Philippines
- Over the last decades, a large body of evidence has already demonstrated the association between traditional tobacco cigarette (TTC) smoking and cardiovascular events.
- More recently, heated tobacco products (HTPs) have been introduced, to potentially reduce exposure to harmful constituents in cigarette smoke and reduce the health burden of smoking-related diseases.
- TTCs and HTPs with outcomes on blood pressure (BP), heart rate (HR), flow mediated dilatation (FMD), pulse wave velocity (PWV), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (Tg) and total cholesterol (TC) were searched through PubMed, Google Scholar and Cochrane database.
- A total of 13 studies were included.
- Pooled analysis of studies showed that HTPs showed significant difference compared to TTCs on HR (MD -3.16 beats per minute [bpm] with 95% CI of -5.41 to -0.91, p=0.006), FMD (in % change) (MD +2.53% with 95% CI of 0.17 to 4.89, p=0.04) and HDL (MD 0.18 mg/dL with 95% CI of 0.07 to 0.28, p=0.0009).
- No significant differences were noted on systolic BP, diastolic BP, LDL, Tg and TC.
- Only 1 study had complete report of outcomes on PWV, showing no significant difference.
Consolidated Forest Plots for Fixed Effects Model (Mean Difference and Standard Mean Difference)
A. Effect Measure of Mean Difference
B. Effect Measure of Standard Mean Difference (HDL)
Forest Plot for Random Effects Model and Effect Measure of Mean Difference (FMD Outcome)
- Evaluating the effects on BP, HR and other known predictors of cardiovascular risk, HTPs, compared to TTCs, showed significant reduction in HR, and significant increases in FMD and HDL cholesterol.
- There are no statistically significant differences in BP, LDL cholesterol, Tg, TC and PWV.
- Larger and long-term studies are still needed to support the cardiovascular benefits of HTPs.
- Although there has already been a great amount of literature on the harmful effects of TTC smoking on cardiovascular health, still relatively less is known about the effects of HTPs on the cardiovascular system especially on BP, heart rate (HR) and other cardiovascular risk predictors.
- Studies such as this, and other bigger RCTs could offer us better knowledge and confidence if switching to HTPs could actually translate to reduced cardiovascular risk particularly in recalcitrant smokers.
A Systematic Review and Meta-Analysis on Human Biomarkers of Exposure from Heated Tobacco Products Compared to Conventional Cigarettes Among Adult Smokers
JDP. Reaño, M.D.1,2, MB Regala, M.D.1,2, RP Arimado1, RR Castillo, M.D.1,2
1 CardioMetabolic Research Unit (CaMeRU), FAME Leaders Academy, Makati City, Philippines
2 Section of Adult Cardiology, Department of Internal Medicine, Manila Doctors Hospital, Manila, Philippines Corresponding author: Joan Dymphna P. Reaño, M.D. (firstname.lastname@example.org); Contact number: +639175089757
Introduction: The health effects of heated tobacco products (HTP), which are non-combustible alternatives to conventional cigarettes (CC), may be assessed by the measurement of biomarkers of exposure (BoE).
Methods: This meta-analysis aimed to compare the BoE levels between HTP and CC. Systematic computerized search was done (Pubmed, Google Scholar, and Cochrane databases). Randomized controlled trials (RCTs) evaluating the effectiveness of HTP compared to CC in reducing human BoE were included. Two reviewers independently appraised each study. Any disparity in assessment was settled by an independent adjudicator. Pooled analyses of studies without significant heterogeneity were based on the fixed effects model.
Results: Data from the trials included in this study (N=1,193) showed that there was a significant difference in the levels of BoEs between HTP and CC. The levels of CoHb [-2.0 (95% CI -3.08 to -0.92), Z=3.64, p=0.00001], 4-ABP [-1.67 (95% CI -2.36 to -0.99), Z=4.80, p=0.00001], 3-HPMA [-1.09 (95% CI -1.54 to -0.63), Z=4.70, p= 0.00001], NNN [-0.95 (95% CI -1.49 to -0.41), Z=3.46, p=0.0005], NNAL [-1.30 (95% CI -1.72 to -0.89), Z=6.18, p=0.00001], TNeq [-0.85 (95% CI -1.36 to -0.34), Z=3.24,p=0.001], 3-OH-BaP [-1.70 (95% CI -2.08 to –1.33), Z=8.92, p=0.00001], and SPMA [-1.18 (95% CI -1.36 to -0.99), Z=12.36, p= 0.0001] among the participants were significantly reduced in those who used HTP as compared to those who smoked CC.
Conclusion:The study showed that the use of HTP could significantly reduce exposure to harmful substances compared to CCs using BoEs as parameters.
Due to the increasing evidence on smoking-related health risks resulting from exposure to toxic compounds from the combustion of conventional cigarette (CC)3-8, heated tobacco products (HTP) were developed.
HTP has been proposed as an alternative to CC to achieve tobacco harm reduction (THR)3,13-16. The underlying concept of THR in tobacco control is that the damage or harm caused by tobacco consumption should be at least reduced when it cannot be totally prevented12,18-20.
Akiyama et al.21 provided a systematic review of available evidence, which showed that HTPs could significantly reduce exposure to harmful substances compared to CCs using biomarkers of exposure (BoE), but with limitation of needing larger and longer-term population-based studies25. Drovandi et al.26 compared BoE levels in humans using HTP versus CC, and the analysis showed significant reductions in BoE levels in those using HTPs compared to CCSs but also noted limitations such as relatively small number of studies, limited BoE ranges assessed, and tobacco industry involvement26.
The commonly-used biomarkers and biomarkers in development are the following: nicotine and tobacco alkaloids, carbon monoxide (CO), tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), aromatic amines and heterocyclic amines, and metals27.
This meta-analysis aims to update the existing literature comparing BoE levels in HTPs versus traditional tobacco cigarette.
To compare the BoE levels between HTP and CC; specifically, using the following parameters: Carboxyhemoglobin (CoHB), 4-aminobiphenyl (4-ABP), 3-hydroxypropylmercaptapuric acid (3-HPMA), N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)- 1-butanol (NNAL), Total Nicotine Equivalents (TNeq), Benzo[a]pyrene (3-OH-BaP), S-phenylmercapturic acid (SPMA).
Criteria for considering studies for this review
- RCTs that evaluated the effectiveness of HTP compared to CC in reducing human BoE were included, if any of the outcomes assessed were: CoHB, 4-ABP, 3-HPMA, NNN, NNAL, TNeq, benzo[a]pyrene, SPMA.
- A total of 8 studies were included
- Two reviewers (JR, MR) independently extracted the data and individually appraised each study, with any disparity in assessment was settled by an independent adjudicator.
- Review Manager 5.3 was used to analyze the data.
Random Effects Model
Fixed Effects Model
Figure 2. Comparison between HTP and CC with the outcomes of different biomarkers using random and fixed effect models
– Meta-analysis of data from the 8 trials included in this study showed that there was a significant difference in the levels of BoEs between HTP and CC. Specifically, the levels of CoHb, 4-ABP, 3-HPMA, NNN, NNAL, TNeq, 3-OH-BaP, and SPMA in the participants were significantly reduced in those who used HTP as compared to those who smoked CC.
– In the analysis of 6 out of 8 outcomes (CoHb, 4-ABP, 3-HPMA, NNN,n NNAL, TNeq), it was noted that significant heterogeneity existed among the included studies, which may be due to the differences in sample size, age range, race of subjects, study duration, and units of measurement among the studies. Nevertheless, in the analysis of 2 out of 8 outcomes (3-OH-BAP and SPMA), there were no issues of heterogeneity.
– Similar to Drovandi et al.26, the studies included in our review were all RCTs. However, during our review, there were other RCTs that were not yet included in their study. Two studies53,58 done in 2012, one study57 in 2013, and one study55 in 2015 were the additional eligible studies included in our systematic review.
– The BoEs analyzed in this study may be the most practical or applicable measures of harm that may be used for regulation of use of tobacco products. In some countries, there is still a paucity of data as to which BoEs are being measured to regulate tobacco products including MRTPs. This study may be a reasonable starting point for HTP regulation by assessing a practical set of BoEs.
– Overall, this study may be supportive of the current developing science involving non-combustible cigarette alternatives.
– HTP may be considered as a promising intervention to reduce the risk of harm in tobacco smokers, especially in recalcitrant smokers.
The study showed that the use of HTP could significantly reduce exposure to harmful substances compared to CCs using BoEs as parameters. The measurement of specific biomarkers (CoHb, 4-ABP, 3-HPMA, NNN, NNAL, TNeq, 3-OH-BaP, and SPMA) may aid our population in the regulation of various tobacco products and their alternatives.