“Smoking Paradox” Stirs Controversy in Stroke Community

"Quit Smoking" also ranks very high in the New Year's resolution statistics. If you are still looking for an excuse to not stop smoking “the smoking paradox” could be it!

Acute and post-treatment day2 images of a non-smoker

 (left) and smoker (right) following middle cerebral artery

 occlusion. Acute perfusion images of non-smoker (1a)

 and smoker (1b) are similar. Angiographies of both patients 

show identical vessel occlusion (arrow, 2a 2b). Following 

 thrombolysis, non-smoker still has occluded vessel (3a), 

yet smoker has recanalized (3b) showing distal blood flow 

restored (arrow heads). Follow-up diffusion image of 

non-smoker shows larger lesion (4a) compared to 

non-smoker (4b).  

A recent study conducted at the Charité re-awakened a hot topic of controversy first described nearly 20 years ago, termed “the smoking paradox” in which smokers respond better to treatment following ischemic cardiovascular events [1].

Smoking is a well-known risk factor for atherosclerosis, myocardial infarction (MI; heart attack) and ischemic stroke. Therefore, it is understandable why the community was unsettled by results published in an observational study in 1995 describing lower mortality rates in smokers with MI following treatment [2].

MI and ischemic stroke are caused by an obstruction of a blood vessel due to a thrombus, or blot clot. The diminished blood flow distal to the occluded vessel causes the downstream tissue to die due to ischemia. The main treatment of these ischemic events is either mechanical removal of the blot clot or lysis of the clot via systemic thrombolysis.  

Following the first study reporting the smoking-paradox in 1995, several studies followed showing similar results. However, a critical review of these studies put a quick end to the discussion; this review attributed the observed better outcome in smokers to their younger age and to insufficient statistical power [3]. Subsequently, the once-hot topic of the smoking paradox fell silent for several years until a recent Charité study stirred up the discussion again with robust results.

In the neuroimaging study at the Charité, smokers with ischemic stroke showed a 6-fold greater chance of recanalization (opening of the occluded artery in response to thrombolysis; see figure) and a trend towards a better recovery compared to non-smokers [1].

STROKE TREATMENT MORE 

EFFECTIVE IN SMOKERS 

Before the study was even accepted for publication, researchers at the Charité got wind of the results and began questioning the findings. Not until an external statistician reviewed the data did the study get the permission to proceed to be re-submitted.

Once accepted for publication in Stroke, the critiques began with similar arguments against the studies in the 90s, namely that statistical power was lacking. It is difficult to argue against these criticisms with one retrospective study. However, it wasn’t long before four further studies followed supporting the theory: smokers respond better to treatment than non-smokers. Although these findings may appear paradoxical at first, there is a feasible scientific explanation.

Experimental animal studies show that smoking decreases the amount of endogenous tissue-plasminogen-activator (tPA) released from endothelial cells [4]; tPA is a protein involved in the breakdown of fibrin, which causes blood to clot. Higher fibrin levels in smokers compared to non-smokers [5] may cause higher risk for thrombus formation. Therefore, the clots formed in smokers may have a higher fibrin content compared to non-smokers, making them more susceptible to be lysed by exogenous tPA treatment (i.e. thrombolysis).  

In light of this possible explanation, the term “smoking paradox” rings quite true. On the one hand, smokers have a higher chance of having a stroke in the first place, but on the other hand have a greater chance of responding to treatment. So, how does this help us in the clinical setting?

PARADOX LINKED TO CLOTS' 

HIGHER FIBRIN CONTENT

Thrombolysis with tPA is not risk-free: approximately 6% of patients suffer an intracerebral hemorrhage. Furthermore, only a small percentage of patients with ischemic stroke arrive to the clinic within the therapeutic time-window of 4.5 hours. Nonetheless, off-label treatment with tPA in tricky cases is quite common. If we know smokers are more likely to respond to treatment, we might have an indication for thrombolysis in potentially difficult cases (i.e. elderly patients, patients arriving in later time-windows).

As of yet, there are only small studies on this topic and results remain controversial. However, recently two large multicenter studies have been launched in order to further investigate the smoking paradox phenomenon, each including >6,000 patients. Hopefully, these studies will unveil the true “smoking effect” and answer the dozens of unanswered questions regarding how we can apply this knowledge in the clinical setting.

[1] Kufner et al, Stroke, 2013
[2] Grines et al, Circulation, 1995
[3] Aune et al, BMC Med, 2011
[4] Newby et al, Circulation, 2011
[5] Barua et al, Arterioscler Thromb Vasc Biol, 2010


by Anna Kufner, PhD Student AG Ebinger
This article was originally published June 2015 in Volume 08, Issue 02 " Art. And the Brain."