Public comment submitted to the FDA: Study abstract, poster and press statement misinterprets the potential effects of IQOS on cardiovascular disease risk
- Friday, 24 November 2017 08:58
By Dr Farsalinos
In relation to my previous blog comment on a study claiming IQOS has similar adverse cardiovascular effects as tobacco cigarettes, I just submitted a public comment to the FDA. Below is the full text of my submitted comment.
Study abstract, poster and press statement misinterprets the potential effects of IQOS on cardiovascular disease risk
Comment Tracking Number: 1k1-8zyw-c5qs
Konstantinos Farsalinos, M.D.
Onassis Cardiac Surgery Center, Greece
University of Patras, Greece
National School of Public Health, Greece
Recently, a study abstract and poster presented at the American Heart Association (AHA) Scientific Sessions 2017 evaluated the acute effects of exposing mice to a heated tobacco product (IQOS) on endothelial function in comparison with a tobacco cigarette (1,2). The study found that IQOS had “the same adverse effects” on Flow-Mediated Dilatation (FMD), a marker of endothelial function, as the tobacco cigarette. The abstract concluded that “Use of HNB tobacco products does not necessarily avoid the adverse cardiovascular effects of smoking cigarettes”. An accompanying press statement concluded with a similar statement: “Using heat-not-burn products may not avoid the adverse cardiovascular effects of smoking cigarettes” (3).
Endothelial dysfunction is considered an important early event in the development of atherosclerosis which precedes gross morphological signs and clinical symptoms (4). Several studies have shown that FMD predicts long-term adverse cardiovascular events both in healthy subjects and in patients with established cardiovascular disease (5-11). There is one common characteristic of all these studies: FMD was measured at resting and carefully controlled conditions and not as an acute response to a stimulus. This is particularly critical and has been addressed in detail in the guidelines for FMD measurements. Specifically, the guidelines published by the International Brachial Artery Reactivity Task Force clearly mention that numerous factors, such as temperature, food, drugs and sympathetic stimuli affect flow-mediated vascular reactivity (12). For this reason, “subjects should not exercise, should not ingest substances that might affect FMD such as caffeine, high-fat foods and vitamin C or use tobacco for at least 4 to 6 h before the study” (12). By definition, measuring FMD after acute intake of a stimulant substance (such as nicotine) is expected to affect the outcome. However, this should not be interpreted as an indication of adverse effect or as a prognostic marker. To the best of my knowledge, no study has ever found FMD to be a prognostic marker of disease when the measurement was made after an acute exposure to a stimulant. It is characteristic that FMD is acutely adversely affected after nicotine intake from nicotine replacement therapies (13). In fact, in response to similar increases in nicotine serum levels, FMD was adversely affected after use of a nicotine nasal spray but the effect was even more pronounced for smoking (13). Coffee intake has also been shown to acutely affect FMD (14,15), although moderate coffee consumption has either no or a protective effect on cardiovascular disease (16). Other acute stressors with no relevance to long-term cardiovascular risk, such as meal consumption (17), also have acute FMD effects. For this reason, measuring acute FMD response to stimuli provides no information about cardiovascular pathophysiology.
The poster of the study in mice exposure to IQOS (2) and the press statement (3), but not the abstract (1), presents some important information on nicotine exposure which makes the study and press statement conclusions particularly problematic and raises concerns about the possibility for experimental error. It is noteworthy that despite exposing mice to the same number of puffs from IQOS and tobacco cigarette, serum nicotine levels in mice were more than 4.5-fold higher after IQOS compared to tobacco cigarette exposure. This is paradoxical because three studies have shown that nicotine delivery to the aerosol of IQOS is substantially lower compared to tobacco cigarette smoke. Studies published by Schaller et al. (PMI), Farsalinos et al. and Bekki et al. have consistently shown an approximately 30% lower nicotine delivery from IQOS compared to 3R4F or commercial tobacco cigarettes (18-20). Therefore, it is unexplained how exposure of mice to IQOS led to 4.5-fold higher serum nicotine levels compared to tobacco cigarette. This fact also violates a basic principle in laboratory studies according to which it is necessary to compare equivalent exposures when evaluating the in vivo or in vitro effects of different products. Therefore, the study conclusion should have mentioned that IQOS has the same acute adverse effect on FMD as tobacco cigarettes when delivering 4.5-fold higher amount of nicotine compared to the tobacco cigarette.
In conclusion, the study assessing the acute effects of IQOS exposure on FMD in mice suffers from serious flaws. The acute effects of an exposure on FMD have no prognostic value for cardiovascular disease and the study findings can be explained by the well and long-established acute sympathetic effects of nicotine. Additionally, exposure to nicotine from IQOS was by far higher compared to the respective exposure from the tobacco cigarette, making any comparisons inappropriate and misleading. Therefore, this study provides no reliable scientific information about the effects of IQOS on cardiovascular disease risk.
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- Nabavizadeh P, Liu J, Ibrahim S, Derakhshandeh R, Springer ML. Inhalation of heat-not-burn tobacco aerosol impairs vascular endothelial function (poster presentation Nov 14, 2017). American Heart Association Scientific Sessions, Anaheim, CA 2017. Available at: https://tobacco.ucsf.edu/sites/tobacco.ucsf.edu/files/u9/iQOS-Poster-11-1-17.pdf.
- American Heart Association. Heat-not-burn tobacco products may be ‘not so hot’ at protecting blood vessel function. Press statement. Available at: https://newsroom.heart.org/news/heat-not-burn-tobacco-products-may-be-not-so-hot-at-protecting-blood-vessel-function.
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