August 21, 2018

Stanton A. Glantz, PhD

Risk of Heart Attacks Is Double for Daily E-Cigarette Users

We just published "Association Between Electronic Cigarette Use and Myocardial Infarction" in American Journal of Preventive Medicine.  Here is the UCSF press release describing the study:

Risk of Heart Attacks Is Double for Daily E-Cigarette Users 
New Analysis Shows Five-Fold Risk for People Who Use Both Cigarettes and E-Cigarettes Daily 

Use of e-cigarettes every day can nearly double the odds of a heart attack, according to a new analysis of a survey of nearly 70,000 people, led by researchers at UC San Francisco. 

The research also found that dual use of e-cigarettes and conventional cigarettes — the most common use pattern among e-cigarette users — appears to be more dangerous than using either product alone. The study found that the risks compound, so that daily use of both e-cigarettes and conventional cigarettes raises the heart attack risk five-fold when compared to people who don’t use either product. 

This is the first study to examine the relationship between e-cigarette use and heart attacks, and begins to fill the understanding of the effects of e-cigarettes on long-term health. The study was published Aug. 22, 2018, in the American Journal of Preventive Medicine. The data were first presented in February in Baltimore at the 2018 annual meeting of the Society for Research on Nicotine and Tobacco.

“Most adults who use e-cigarettes continue to smoke cigarettes,” said senior author Stanton Glantz, PhD, a UCSF professor of medicine and director of the UCSF Center for Tobacco Control Research and Education.  

“While people may think they are reducing their health risks, we found that the heart attack risk of e-cigarettes adds to the risk of smoking cigarettes,” Glantz said. “Using both products at the same time is worse than using either one separately. Someone who continues to smoke daily while using e-cigarettes daily increases the odds of a heart attack by a factor of five.”

But the research also reported some good news if smokers quit:

“The risk of heart attack starts to drop immediately after you stop smoking,” said Glantz. “Our results suggest the same is true when they stop using e-cigarettes.”

Electronic cigarettes typically deliver an aerosol of nicotine and other flavors by heating a liquid and are promoted as a safer alternative to conventional cigarettes, which generate the nicotine aerosol by burning tobacco. 

While e-cigarettes deliver lower levels of carcinogens than conventional cigarettes, they deliver both ultrafine particles — which are 1/50 to 1/100 the size of a human hair — and other toxins that have been linked to increased cardiovascular and non-cancer lung disease risks. 

The new analysis involved 69,452 people who were interviewed through National Health Interview Surveys in 2014 and 2016, a cross-sectional study in which in-person interviewers asked participants whether they had ever used e-cigarettes and/or cigarettes, and whether they had ever been told by a doctor or other health professional that they had had a heart attack.

Among the 9,352 current and former e-cigarette users, 333 (3.6 percent) had experienced a heart attack at some point, with the highest percentage (6.1 percent) among those who used e-cigarettes daily. In the analysis, a quarter of the 2,259 people who currently used e-cigarettes were former smokers of conventional cigarettes and about 66 percent of current e-cigarette users were also current cigarette smokers. 

The researchers found that the total odds of having a heart attack were about the same for those who continued to smoke cigarettes daily as those who switched to daily e-cigarette use. For those who used both products daily, the odds of having had a heart attack were 4.6 times that of people who had never used either product. 

The authors also said that that while there was a “lasting effect” associated with being a former smoker, there was not a significant increase in myocardial infarction risk for former or (sometimes) e-cigarette users. They proposed that the risks of e-cigarette use may dissipate rapidly when someone stops using them, that some people briefly experiment with e-cigarettes and stop using them before any lasting damage is done, or that e-cigarettes have not been available long enough to cause permanent damage to the cardiovascular system. 

“The only way to substantially reduce the risk of a heart attack is to stop using tobacco,” Glantz said.   

The authors noted that it was not known whether the heart attacks occurred relative to e-cigarette use, and that some of the heart attacks that subjects reported are likely to have occurred before e-cigarettes became available in the U.S. (around 2009), which would lead them to underestimate the effects of e-cigarettes on heart attack risk.

The paper’s co-authors are Talal Alzahrani, MD, Ivan Pena, MD, and Nardos Temesgen, MD, all of George Washington University. Glantz’ work was supported by grant R01DAO43950 from the National Institute of Drug Abuse and P50CA180890 from the National Cancer Institute and the Food and Drug Administration Center for Tobacco Products.


Here is the abstract from the paper:

Introduction: Electronic cigarettes (e-cigarettes) are promoted as a less risky alternative to conventional cigarettes and have grown in popularity. Experimental and clinical evidence suggests that they could increase the risk of myocardial infarction.
Methods: The National Health Interview Surveys of 2014 (n=36,697) and 2016 (n=33,028) were used to examine the cross-sectional association between e-cigarette use (never,former,some days, daily) and cigarette smoking (same categories) and myocardial infarction in a single logistic regression model that also included demographics (age, gender ,BMI) and health characteristics (hypertension, diabetes, and hypercholesterolemia) using logistic regression. Data were collected in 2014 and 2016 and analyzed in 2017 and 2018.
Results: Daily e-cigarette use was independently associated with increased odds of having had a myocardial infarction (OR=1.79, 95%CI=1.20,2.66, p=0.004) as was daily conventional cigarette smoking (OR=2.72, 95%CI=2.29,3.24, p<0.001). Former and some day e-cigarette use were not significantly associated with having had a myocardial infarction (p=0.608 and p=0.392) whereas former (OR=1.70, p<0.001) and some day cigarette smoking (OR=2.36, p<0.001) were. Odds of a myocardial infarction were also increased with history of hypertension (OR=2.32, p<0.001); high cholesterol (OR=2.36, p<0.001); and diabetes (OR=1.77, p<0.001); and age (OR=1.65 per 10 years, p<0.001). Women (OR=0.47, p<0.001) had lower odds of myocardial infarction.
Conclusions: Daily e-cigarette use,adjusted for smoking conventional cigarettes as well as other risk factors, is associated with increased risk of myocardia linfarction.

The full citation is:  Talal Alzahrani, Ivan Pena, Nardos Temesgen,Stanton A. Glantz.  Association Between Electronic Cigarette Use and Myocardial Infarction. Am J Prev Med 2018; Published online ahead of print 22-AUG-2018 DOI information: 10.1016/j.amepre.2018.05.004.  It is available here



The study has a cross-sectional design, which is not appropriate for the assessment of causal-effect relationships. In addition, outcome evaluation is weak, and the overall conclusions are at a very high risk of bias. I am surprised that the American Journal of Preventive Medicine published these results with such an emphasis.


These are all the standard criticisms we anticipated from e-cigarette advocates.  Here are the responses:

1. We did not say the association was causal.  In fact we took care not to.  What we did say is that the observed association is exactly what you would expect based on the demonstrated biological and clinical effects of e-cig exposure on the cardiovascular system.

2. The quiestion used to assess whether people had a heart attack is the standard question used on federal and other surveys and, as described in the paper, has been validated against medical records years ago.  That is why the CDC, FDA/NIH PATH study, and others use it.

3.  Issues of bias are also addressed in the paper.  Simply saying there is bias does not demonstrate that it exists.  Critics need to present evidence that such assertions are actually correct.  The one source of bias that is important -- and which is discussed in the paper -- is the fact that some of the heart attacks occurred before the advent of e-cigarettes biases the risk estimates to the null, i.e., means that we are probably underestimating the effect of e-cigarette use on heart attack risk.


This is an interesting study that raises important questions about e-cigarette safety in the longer term.

Did you collect data about the type of device or the nicotine content of the fluid being used as US ejuice often has higher levels of nicotine that the UK


Unfortunately, the National Health Interview Survey does not collect that level of detail.

The ultrafine particles and some of the other chemicals in e-cig aerosol are important causes of the cardiovascular effects, and these are more-or-less the same in all e-cigs.  That is how they work.  Nicotine is also important, but small differences in nicotine levels probably are less important than these other factors which are common to all e-cigs.


ASH responds predictably

ASH England, among the world's greatest cheerleaders for e-cigarettes, posted the following report in its news feed:

USA: Study finds vapers who use e-cigarettes every day are at higher risk of heart attack

Researchers analysed the 2014 and 2016 results of The National Health Interview Survey, which includes interviews from adults living in the US. Some 69,452 participants were asked: 'Have you ever been told by a doctor or other health professional that you had a heart attack (also called myocardial infarction)?'. The analysis of the increased risk of heart attacks was based on answers to this question.  

The researchers found that people who smoke tobacco and use e-cigarettes were most likely to have had a heart attack. 

Editorial note: This study does not establish a causal relationship between heart attacks and the use of e-cigarettes. Rather it shows that at the point they were surveyed people who smoked and/or vaped were more likely to have had a heart attack in their lifetime. The study was not able to determine when the heart attack took place, whether it followed or preceded use of an e-cigarette. It is therefore inaccurate to say this research shows that vaping leads to an increased risk of a heart attack. The link between tobacco smoking and heart attacks is well established. See our fact sheet for more information. ASH fact sheet: Smoking, the Heart and Circulation.

Source: Daily Mail, 23 August 2018

Interestingly, ASH England spent 88 words summing up the study and 111 words trying to dismiss the findings.  Like all e-cig cheerleaders, they make the point that you cannot use the "cause" word based on a cross-sectional study (which is why we didn't say "cause").  They also recite all the usual concerns with cross-sectional studies.

They ignore the fact that well-done cross-sectional studies are the first step to identifying relationships worthy of exploring in longitudinal studies.  Longitudinal studies, because they involve following the same people for years, take years to do.

So, ignoring or downplaying cross-sectional studies is a standard strategy for ignoring evidence you don't like.  ASH England did this when the first cross-sectional studies were published suggesting that e-cigs are a gateway to cigarettes.  Even though there are a ton of longitudinal studies showing the gateway effect, ASH England keeps trying to downplay them, too.

ASH England also ignores the fact that the association we found is exactly  what one would expect based on the known adverse biological effects of e-cigs on blood vessels and the cardiovascular system.

But they have lots of friends in England. 

The question is how many people will e-cigs have to kill before they start looking at what the evidence shows rather than trying to explain it away.


Reverse causality: Another excuse to ignore the evidence falls

So far, most of the evidence on long-term adverse effects of e-cigarettes has been from cross-sectional studies, as our recent paper showing that people who used e-cigarettes were more likely to have had heart attacks, which represent a “snapshot in time.”

As a result one can only talk about “associations” not “cause” because there is always the possibility of so-called “reverse causation.”  If this case, reverse causation would exist if people who had heart attacks were subsequently more likely to start using e-cigarettes than people who had not had heart attacks.  In such a situation the association that we found would be due to this effect rather than e-cigarettes causing heart attacks.

Indeed, the possibility of reverse causation is one argument that e-cigarette enthusiasts have been using to dismiss  a wide range of studies implicating e-cigarettes on everything from health effects to the gateway effect they have for kids (starting with e-cigarettes, then adding or switching to cigarettes).

Holly Middlekauff and Jeffrey Gornbeing wrote a letter to the editor of American Journal of Preventive Medicine, where we published our paper.  Our response cites longitudinal data from the PATH study showing that people who have had a heart attack are no more likely to start using e-cigarettes than people who have not had a heart attack.  Our cross-sectional data also showed that e-cigarette use was not associated with making a quit attempt among people who had a heart attack.

Thus, reverse causality is unlikely to explain the association we found between e-cigarette use and having had a heart attack.  Significantly, this risk is on top of any risks of smoking cigarettes, which means that dual use – when people use both products at the same time (the most common pattern) – is more dangerous than using either one alone.

PS: Another word game that e-cigarette enthusiasts have use to criticize cross-sectional studies is use of the term “risk factor,” which they say implies causality.  It does not.  Indeed, the term “risk factor” was developed specifically to refer to associations in cross-sectional studies.


E-cig advocates now arguing about what “risk” means.  Konstantinos Farsalinos and Raymond Niaura just published a letter to the editor in American Journal of Preventive Medicine criticizing our paper linking e-cigarette use with heart attacks on the grounds that we used the term “risk factor” to describe the cross-sectional association between e-cig use and having had a heart attack.

As we point out in our response, the term “risk factor” was specifically developed to describe associations found in cross-sectional studies.  (Wikipedia has a nice explanation of this point.)  We also noted that the association we found in the population is precisely what would be expected based on the known biological and clinical effects of e-cigarette use on the cardiovascular system.

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