[updated 27 March, 2020]
Since I published this blog this time last year, I’ve seen a further critique written by Prof Matthew Peters, a respiratory specialist from Sydney’s Concord Hospital and former chair of Action on Smoking and Health Australia. Here it is, with the original blog following below)
Electronic cigarettes vs NRT for smoking cessation – the sting is in the tale.
In February 2019, Hajek and others published results of a randomised trial of nicotine replacement therapy (NRT n=446) vs use of a second-generation refillable e-cigarette device (n=438) in the New England Journal of Medicine. Subjects were all self-selecting attenders at U.K. National Health Service stop-smoking services.
The paper attracted considerable attention as it was a randomised study with an active control arm and used modern e-cigarette (EC) devices. Compared to the few previous randomised trials which used earlier generation ECs, it had a substantially greater effect size with relative risk of 1.75-1.84, (depending on adjustments and exclusion of certain subjects) for the primary outcome variable of continuous abstinence at 52 weeks. In media discussions since, this effect was commonly rounded up to a doubling of smoking cessation compared to NRT.
Three other smoking cessation outcomes were also reported or calculable from data in the paper and the associated supplement.
- Intention to treat (ITT) allocation to EC was not associated with reduced risk of relapse beyond 4 weeks after the target quit date. This was so even though EC use continued at a rate of 40% vs 4% for NRT.
- The relative risk (RR) for 7 days point-prevalence abstinence at 52 weeks was 1.52 for EC vs NRT
- The RR for continuous abstinence and being smoke and nicotine free at 52 weeks was approximately 0.5 for EC vs NRT. The ITT e-cigarette arm had 14 (3.1% smoke-free/nicotine free subjects compared to 31(6.9%) in the NRT arm.
If the beneficial effect is based on factors within the first 4 weeks, it is critical to exclude biases in the administration of the intervention and control treatments and to consider whether there may have been participant biases. Here, it is a problem that the control intervention was poorly applied. In the first 4 weeks, only 10% reported use of NRT daily vs 53% for those randomised to e-cigarettes. 25% of the NRT subjects used it on 19 or fewer days.
The investigators sought per protocol to exclude potential participants who may not have been equally disposed to one or other treatment but probably did not succeed. 91 NRT subjects did not complete 4-week follow-up compared with only 63 with e-cigarettes and these were counted as continuing or relapsed smokers as is standard practice in trials. Reinforcing the probability that the participating subjects were more favourably disposed to EC than NRT, crossover from NRT to e-cigarettes occurred around three times more often than e-cigarettes to NRT. In contrast, there was no difference for varenicline.
Critically, a statistical oddity underpins the high relative risk for continuous abstinence at 52 weeks. Continuous (CA) or prolonged abstinence and CO-confirmed 7-day point prevalence abstinence (PPA) are equally valid, highly correlated smoking cessation study end-points. CA cannot, by definition, exceed PPA. Hughes and others found a ratio of 0.74 from a systematic review of smoking cessation intervention studies. Viewing consolidated data from the paper and supplement in one table provides the best insight into the problem.
|PPA- EC (n)||CA-EC(n)||CA/PPA Ratio||PPA-NRT(n)||CA-NRT(n)||CA/PPA Ratio||RR for PPA
|RR for CA
Abbreviations used: CA continuous abstinence; PPA point prevalence abstinence; RR relative risk
What is clear that a dramatic fall at 52 weeks in CA/PPA for e-cigarettes and an even greater fall for NRT were required to achieve the headline relative risk for continuous abstinence with both ratios being well outside Hughes’ mean estimate. It is possible that the standard for continuous abstinence (not more than 5 cigarettes after quit date) contributed to CA/PPA being so different at 52 weeks compared to 26 weeks but this does not explain why the decline for NRT was so much greater.
Until this anomaly is explained, we are left with the more solid smoking cessation data being 7-day point prevalence CO-confirmed abstinence. That figure of about 1.5 at 52 weeks could still suggest that high nicotine delivery systems outperform older generation e-cigarettes for cessation outcomes but this finding would still need to be considered in the light of sharp differences in the application of e-cigarettes and NRT control in the critical first 4 weeks.
Importantly, all trial participants also received “weekly behavioural support for at least 4 weeks”, with the authors noting in their conclusion that “E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support.”. This support “involved weekly one-on-one sessions with local clinicians, who also monitored expired carbon monoxide levels for at least 4 weeks after the quit date.” Eighty one percent of participants received 4 or 5 support sessions.
However, in real world use of either NRT or ecigs for smoking cessation, only a very small proportion of smokers would receive such support. Important questions therefore arise about the relative contributions of NRT and ecigs, to that of the support which all received. A study of a national English prospective cohort of 1560 smokers found “the adjusted odds of remaining abstinent up to the time of the 6-month follow-up survey were 2.58 (95% CI, 1.48-4.52) times higher in users of prescription medication in combination with specialist behavioral support”. However “The use of NRT bought over the counter was associated with a lower odds of abstinence (odds ratio, 0.68; 95% CI, 0.49-0.94).” This suggests that real world use of NRT without support may be ineffective.
Serious adverse events
The notion that new-generation e-cigarettes would be able to deliver more of the “good stuff”, nicotine, and not more of the bad stuff – toxic products of superheated vehicle solvents and flavourants was always questionable. This study reports numerically more serious adverse events in the e-cigarette arm than the NRT arm – 27 vs 22. Excluding malignancies, there were 7 potentially smoking related serious adverse events (SAEs) – one fatal- in the e-cigarette arm and 4 in the NRT group even though smoking rates remained higher in the NRT arm. Of the 5 respiratory events with e-cigarettes (vs 1 with NRT), the investigator concluded in each case that e-cigarette use was unrelated. The risk disparity 1.1% vs 0.2% was in the authors’ published conclusion – “likely a chance event”. This would suggest that there is a lack of objectivity and/or openness to emerging risks of e-cigarettes.
These safety findings are consistent with the failure of e-cigarette use, whether as complete or partial substitution for smoking, to reduce potential smoking-related disease or to meaningfully improve general health in a 4-year prospective study. Here with no reduction in potentially smoking related serious adverse events and an imbalance in respiratory SAE’s, serious doubts are created in relation to claims that use of latest generation e-cigarettes is 95% safer than smoking; if it is safer at all.
The New England Journal of Medicine has just published the results of a randomised controlled trial on the relative efficacy of e-cigarettes v nicotine replacement therapy.
Here are the results and conclusions from the abstract (the full article is paywalled).
Results A total of 886 participants underwent randomization. The 1-year abstinence rate was 18.0% in the e-cigarette group, as compared with 9.9% in the nicotine-replacement group (relative risk, 1.83; 95% confidence interval [CI], 1.30 to 2.58; P<0.001). Among participants with 1-year abstinence, those in the e-cigarette group were more likely than those in the nicotine-replacement group to use their assigned product at 52 weeks (80% [63 of 79 participants] vs. 9% [4 of 44 participants]). Overall, throat or mouth irritation was reported more frequently in the e-cigarette group (65.3%, vs. 51.2% in the nicotine-replacement group) and nausea more frequently in the nicotine-replacement group (37.9%, vs. 31.3% in the e-cigarette group). The e-cigarette group reported greater declines in the incidence of cough and phlegm production from baseline to 52 weeks than did the nicotine-replacement group (relative risk for cough, 0.8; 95% CI, 0.6 to 0.9; relative risk for phlegm, 0.7; 95% CI, 0.6 to 0.9). There were no significant between-group differences in the incidence of wheezing or shortness of breath.
Conclusions E-cigarettes were more effective for smoking cessation than nicotine-replacement therapy, when both products were accompanied by behavioral support.
This study is already causing the predicted outbreak of gushing hyperbole from e-cigarette interests and their urgers.
Professor Martin McKee, from the London School of Hygiene and Tropical Medicine, has shared the following comments about the paper that are very useful.
“The subjects were people who had already decided to attend a stop smoking service. Then, randomisation only began after they had set a quit date. In other words, they were very far from a random sample of smokers. They also excluded existing dual users. [note dual e-cig and cigarette use is by far the most common way that e-cigarettes are used].
Outcome was self-reported use of less than 5 cigarettes from 2 weeks post enrollment to 1 year, and validated, but only by 1 biochemical (CO) test at 1 year, which would only capture very recent smoking.
Among those who did give up, 80% in the e-cig group were still using them, but only 9% of the NRT group were using NRT. Given evidence from other studies, such as the US PATH study, that over longer periods quite a lot of e-cig users relapse, it will be important to look at longer term follow up. (The authors say 80% is “fairly high”!)
They say “Provided that ongoing e-cigarette use has similar effects to long-term NRT…” but then refer to 1988 study. And they say nothing about health risks of e-cigs.
Finally, as they note, this study is inconsistent with 3 previous ones.
So, in summary, I would say:
“This study differs from previous ones in finding that e-cigarettes do seem to be better than NRT at maintaining abstinence, at least for one year, in a highly selected group of people who have already decided to quit and have taken steps to get help with it. Of course, the vast majority of those who quit do so unaided, but, nonetheless, these findings are interesting, although it will be important to see what happens in the longer term. It is, however, important to recognise that it only relates to those who are using e-cigarettes when linked to face-to-face support from a smoking cessation service. It tells us nothing about their use in the wider population of smokers, which is where many of the concerns lie.”
Here’s another comment
“E-cigarettes may be better than the nicotine replacement alternative in the [NEJM] study — but they only helped a minority of participants in the vaping group quit. “In spite of the concerted effort and encouraging findings, it is still disappointing,” said David Liddell Ashley, the previous director of the office of science in the Center for Tobacco Products at FDA [Food & Drug Administration]… So this randomized controlled trial might — and probably should — encourage health professionals to consider e-cigarettes, at least the type shown to be effective in the study, as a tool for their smoking patients. But it also shows e-cigarettes are far from the panacea some suggest they might be.” [Julia Belluz. Study: Vaping helps smokers quit. Sort of. Vox]
Behavioural support: little real world relevance
To this I would emphasie that the participants in the trial received not only e-cigarettes or NRT, but they self-selected to attend a quit smoking service and received “behavioural support”. This means these subjects were very different to random e-cigarette or NRT users in the English community, the great majority of whom do not elect to attend such services.
In Australia, despite the quitline phone number being on every cigarette pack and it being hammered in many quit smoking campaign ads, only 3.6% of smokers ever called the quitline over a year. Far fewer are interested in attending “behavioural support” sessions. So this paper has very important limitations in its relevance for debates about whether e-cigarettes (or NRT) can assist people to quit under conditions of real world use.
We know from recent real world longitudinal studies of people who vape in the USA that e-cigarette users actually do worse with quitting than those who use other forms of smoking cessation aids, and particularly those who quit unaided. I covered this in an earlier blog here.
We also know that over-the-counter NRT, used without support in the normal way that nearly all users use it, is not effective. See for example here (“The use of NRT bought over the counter was associated with a lower odds of abstinence (odds ratio, 0.68; 95% CI, 0.49-0.94).). In other words, using NRT like this might actually prevent quitting. Big Tobacco, now with major investments in e-cigs and heat-not-burn products, will be praying the same thing is true for e-cigs. And if they are wise investors, also very confident that the net effect of e-cigarette proliferation will be to keep far more people in smoking than are tipped out of it, and that it will provide nicotine addiction training wheels to many children who have never smoked and probably never would have.
Thomas Eissenberg said:
I am not sure what all the fuss is about.
I am not at all surprised that an ECIG that delivers nicotine effectively (not sure if this one did, but the results suggest that it may have) would be an effective cessation aid. Why wouldn’t it?
I am not at all surprised that an ECIG that delivers nicotine effectively (not sure if this one did, but the results suggest that it may have) would be MORE effective as a cessation aid than standard NRT (e.g., gum, patch, lozenge) — a variety of studies have demonstrated that there are ECIGs that deliver nicotine faster than NRT and with many of the cues of a combustible cigarette: at least one study shows that ECIGs that deliver nicotine suppress tobacco/nicotine withdrawal (in cigarette smokers) really well, in a manner that increases as nicotine delivery to the blood increases.
I do have concerns that the behavioral intervention provided may have been biased, given the likelihood of unblinded status of the therapists, but let’s put that concern aside for a moment.
What does this study tell us? It tells us that if ECIGs are to be used as therapy, they should be ECIGs that deliver nicotine effectively and used in conjunction with meaningful behavioral intervention, not ECIGs that do spaghetti-monster-knows-what, sold in convenience stores running on a business model that emphasizes the fast buck/pound/peso/lira more than it does helping smokers quit. It hints (along with the extant literature showing that dual use is the norm) that the “wild west” method of ECIG sales is likely not helping consumers. It tells us that, if ECIGs are to be in any way helpful, strict regulation and not free market economics is warranted. And, of course, it should call to mind the obvious fact that addictive drugs should not be sold to non-addicted individuals for whom they have no benefit.
The results of the study are eminently predictable…trials that included devices that did not deliver nicotine showed that those devices are not helpful in terms of smoking cessation, and trials that include devices that do deliver nicotine (I don’t know that these did) are likely to show that ECIGs can be helpful in terms of smoking cessation, especially when coupled with intensive behavioral therapy.
Let us please not deny scientific plausibility when we see it. In an ideal world, ECIGs would have been vetted prior to marketing so that we know which ones work (work=help smokers quit), for whom they work, in what context they work, and how they should be regulated to ensure the greatest benefit at the least cost.
Wasim Maziak said:
We know clinical trials are very selective in their subjects and settings which decrease their real-world validity. This is similar to when we found out that NRT in the real world is not effective compared to their record in RCTs. This was coming and it is not the real problem with e-cigarettes but the recruitment of never smokers, and the fact that the industry that e-cigarettes was supposed to “disrupt” is buying up their disruptors. Surprise!!!
Those who made careers promoting NRT, and medicalizing (billing) nicotine addiction and treatment will be sure jump on this after they figured out that they cannot teach their old NRT dog any new tricks. You see 100% similarity in NRT and e-cigarettes promoters, so evidence is not going to dissuade people here. In a sense history repeats itself with a painful mundanity.
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John R. Polito said:
Let me see if I’ve got this funky math right. E-cig advocates are tonight celebrating the fact that 16 of 443 e-cig users successfully arrested their chemical dependence upon nicotine (79 stopped smoking versus 63 still vaping), while NRT advocates are hanging their heads after nearly 3 times as many — 41 of 443 — are at one year living 100% nicotine-free lives (44 quit smoking with 4 hooked on the cure).
Turning from dependency to harm, while e-cigs generated 1.8 times more ex-smokers, what if vaping is 1.8 times more destructive to the human organism than NRT, is it a push/wash? Don’t laugh. It’s as “science-based” as someone with zero long-term data pulling out of their butt an assertion that vaping is 95% safer than smoking.
While e-cigs prevailed over NRT in the Weaver 2018 PLoS One study too, the margin there was much closer, while cold turkey clobbered both.
Why is pharma’s army of cessation consultants so excited? Wouldn’t you be elated too if you’d devoted decades to shouting NRT “doubles your chances,” only to see a Gallup Poll in which nearly all successful ex-smokers quit without use of any approved product? Seriously, I’ve often wondered how they sleep at night.
Here in the U.S., we’re now watching Chantix “slow turkey” commercials. They’re brilliant. They tell a drug addict that they can continue using their drug while getting used to Chantix, while comparing use of a dopamine receptor partial agonist to abrupt nicotine cessation, the smoker’s natural cessation instinct. Have your cake while trusting your instincts too.
The common thread between e-cigs, NRT and Chantix is that they play and prey upon a true drug addict’s mental illness, the fact that their brain sees and treats nicotine as if food.
Instead of helping smokers appreciate that the chains that bind them are primarily the collective influence of thousands of salient use memories documenting how urges for more were almost instantly satisfied, and that saying “no more” and coming home is good and wonderful not bad, the neo-nicotine industry, while co-opting “cessation,” is doing its darnedest to match smoked nicotine’s bolus.
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