INTRODUCTION

Electronic cigarettes (e-cigarettes) are an electronic product consisting of 3 major components: a rechargeable battery, a smoke producing device, and an inhalation box¹. The ingredients of inhalation mainly consist of edible glycerol, edible propanediol, edible propanetriol and edible essential oils². Compared to combustible cigarettes, e-cigarettes have no tar, nicotine, or carbon monoxide in inhalation. Therefore, the initial purpose of e-cigarettes is to help smokers or nicotine dependents quit smoking and reduce organ damage caused by smoking³. To obtain a more realistic feeling as if smoking combustible cigarettes, different proportions of nicotine are added to e-cigarettes⁴. In addition, a plethora of design features have led to an increase in smoking e-cigarettes among youth⁵. However, e-cigarette use may be related to other substances^6,7. Ingredients of smoke produced by e-cigarettes may not only injure the lung but also can enter the circulatory system via gas exchange in alveoli, thus inducing cardiovascular risk^8,9.

Stroke, as a common cerebrovascular disease, has a high mortality and disability rate. Although many studies have reported that using e-cigarettes was associated with occurrence of stroke, some studies have concluded that e-cigarettes may help smokers stop using combustible cigarettes and reduce the risk of stroke^10,11. Therefore, we aimed to perform a systematic review and meta-analysis of clinical epidemiology studies that assessed the association between stroke and e-cigarette use.

METHODS

This systematic review and meta-analysis was performed referring to the protocol published in the database of International Platform of Registered systematic review and Meta-analysis Protocols (INPLASY, https://inplasy.com/, registration number: INPLASY202180086, DOI number: 10.37766/inplasy2021.8.0086.)

RESULTS

Totally, 1697 articles were retrieved from 3 databases according to the search strategy. After further screening according to the inclusion and exclusion criteria, 6 articles^11-16 of cross-sectional studies were finally included (Figure 1). There were 1134896 participants in the 6 included studies (Table 1). The age range was 15–78 years. Males were close to 50%. Periods of observation were from 1 to 4 years. Different solutions of combustible cigarette smoking and e-cigarette use could be classified into 6 types: 1) neither e-cigarette nor combustible cigarette use; 2) currently e-cigarette use only but formerly combustible cigarette use only; 3) combustible cigarette use only; 4) e-cigarette use only; 5) both of e-cigarette and combustible cigarette use; and 6) solutions of combustible cigarette smoking and e-cigarette use were not separated, including 2), 4) and 5). Thus, different data were extracted from the same article. One study (2021 Reynolds) divided the type 6) solution into 3 sub-solutions: 1. Frequency of e-cigarette use > frequency of combustible cigarette smoking, 2. Frequency of e-cigarette use < frequency of combustible cigarette smoking, and 3. Frequency of e-cigarette use = frequency of combustible cigarette smoking, which produced 3 data extractions. One study (2021 Bricknell) divided the type 4) solution into 3 sub-solutions: e-cigarette use only every day, e-cigarette use only sometimes, e-cigarette use formerly.

Figure 1

Process of literature search

Because all the articles were cross-sectional studies, only AHRQ was used to assess their quality. One study (2019 Osei) was assessed as ‘Yes’ in every section, which had the highest quality (Table 2). In subjective influence section, one article (2020 Sverre) was assessed as ‘No’. Five articles were assessed as ‘No’ in the quality assurance section. In the data missed section, two articles were assessed as ‘No’. All the studies were assessed as ‘No’ in the follow-up section. Finally, one article (2020 Sverre) was assessed to have 6 ‘Yes’, which had the lowest quality. Only ORs directly appeared in articles, which were extracted by us to perform the next stage of data analysis.

The total pooled OR was 1.25 (95% CI: 1.01–1.55) with heterogeneity of I²=96.6% (p<0.001) (Figure 2). In the sensitivity analysis, after omitting the study with the highest quality (2019 Osei), pooled OR was 0.99 (95% CI: 0.96–1.04) with a heterogeneity of I²=83.4% (p<0.001). There was a symmetrical distribution in the funnel plot (Figure 3). The study with the lowest quality (2020 Sverre) might have resulted in the high heterogeneity of total pooled OR; after omitting this study, the pooled OR was 1.23 (95% CI: 1.19–1.28) with a heterogeneity of I²=96.8% (p<0.001). However, heterogeneity was still high. Referring to combined combustible cigarette smoking and e-cigarette use, we performed subgroup analysis of total ORs. Compared to neither e-cigarette nor combustible cigarette users, pooled OR of stroke occurrence in current e-cigarette only users was 1.13 (95% CI: 0.99–1.29) (I²=45.9%, p=0.116). Compared to combustible cigarette only smokers, pooled OR of stroke occurrence in dual e-cigarette and combustible cigarette users was 1.39 (95% CI: 1.19–1.64) (I²=5.6%, p=0.303). In addition, pooled OR in currently e-cigarette only users who were formerly combustible cigarette only smokers was 1.59 (95% CI: 1.22–2.07) (I²=0.0%, p=0.989). Compared to neither e-cigarette nor combustible cigarette users, pooled OR of stroke occurrence in e-cigarette users who did not clearly distinguish the use of combustible cigarettes was 0.94 (95% CI: 0.79–1.13) and pooled OR in both e-cigarette and combustible cigarette users was 1.95 (95% CI: 1.06–3.61) with a heterogeneity of I²=87.1% (p<0.001) and I²=98.1% (p<0.001) (Figure 4). Compared to combustible cigarette only smokers, only one OR of stroke occurrence in e-cigarette only users was 0.43 (95% CI: 0.20–0.93). Compared to neither e-cigarette nor combustible cigarette users, pooled OR in current e-cigarette only users who were formerly combustible cigarette only smokers was 2.54 (95% CI: 1.16–5.56).

Figure 2

Totally pooled OR of stroke occurrence in e-cigarette users

Figure 3

Funnel plot of all the ORs extracted from articles

Figure 4

Subgroups analysis of totally pooled OR

DISCUSSION

Our results of total pooled OR showed that the role of e-cigarettes as a risk factor for stroke is inconclusive due to the strong effect of prior tobacco use. However, publication bias and the data from the study with the lowest quality were not the source of significant heterogeneity. Finally, results in subgroup analysis support that one source of heterogeneity was the ambiguous solutions of combustible cigarette smoking and e-cigarette use. Moreover, due to the specific limitations of the cross-sectional study, we could not judge the causal and chronological ordering relationship of e-cigarette use and other risk factors of stroke occurrence such as hypertension, diabetes, auricular fibrillation, which might be other sources of heterogeneity. Compared to combustible cigarette only use, current e-cigarette only users with formerly combustible cigarette only smoking would face the risk of stroke occurrence, which might confirm that e-cigarette use as a replacement or adjunctive therapy for quitting smoking, could not reduce the risk of stroke occurrence. However, compared to neither e-cigarette nor combustible cigarette users, e-cigarette only use might not be the risk factor for stroke occurrence.

Smoke produced by e-cigarettes could injure the blood-brain barrier^17,18 and lead to neuroinflammation¹⁹. In addition, e-cigarette exposure could influence cognitive functions²⁰ and decrease brain glucose utilization in ischemic stroke²⁰, which might lead to an unfavorable prognosis for stroke patients. We considered that blood vessel endothelia had been damaged via smoking combustible cigarettes. E-cigarette use might further deteriorate the injury of cerebrovascular endothelium in current e-cigarette users who smoked combustible cigarettes currently or formerly. Although e-cigarette only use might not be the risk factor for stroke, it might be associated with other diseases such as cancer, heart and lung diseases^21,22. Therefore, the better choice for quitting smoking or nicotine might be to immediately stop using e-cigarettes and smoking combustible cigarettes, which might be a better way to reduce organ injuries.

CONCLUSIONS

The role of e-cigarette use on the development of stroke is inconclusive, due to the strong effect of prior tobacco use as a risk factor for stroke, in the included studies.