Basilar artery occlusion and unwarranted clinical trials

In the beginning of the 1950s, the tobacco industry faced a dangerous threat. Lung cancer incidence was rising in large parts of the world, and a growing number of observational studies claimed that this was due to the popular habit of cigarette smoking. The answer from the tobacco industry was swift, and at a meeting in the Plaza Hotel in New York in December 1953, executives from the leading tobacco companies gathered with representatives from the Hill & Knowlton public relations firm to set up strategies to counter the new body of evidence.¹ As a result of this meeting, the Tobacco Industry Research Committee was created. The purpose of this institution was to discredit the science behind the linkage of cigarette smoking to lung cancer.¹ In the aftermath of the Second World War and the experiments conducted on humans in prisons and concentration camps, it was evident that no researcher would want to conduct, and that the newly adopted Nuremberg code would not allow, a randomized trial on humans on whether cigarette smoking causes lung cancer or not. Thus, creating doubt and mistrust towards the alternative to randomized trials, i.e. observational studies (cohort and case control studies), was a main objective. This was done by sponsoring studies that would generate conflicting results, challenging findings deemed negative for the tobacco industry, branding observational studies as untrustworthy through media campaigns, and labeling studies as “junk science”, to name a few of the strategies used. The efforts continued through the decades, and in 1993, Philip Morris set up a World Regulatory Affairs (WRA) department for “the strategy and coordination of activities relating to environmental tobacco smoke and the social acceptability of smoking”. This department had a budget of $66.1 million and it sponsored programs of “Sound Science” and “Good Epidemiological Practice”. To counter an international observational study on second hand smoke exposure and risk of lung cancer that was funded by the International Agency for Research on Cancer with an estimated cost of $ 1.5 to 3 million over 10 years, WRA spent $ 2 million in 1993 alone.^2,3

Today, thanks to the Tobacco Master Settlement Agreement that forced public display of previously secret internal tobacco industry documents, all this is known.⁴ Unfortunately, however, the effects of the smearing campaign against observational research still linger, and notably so in certain parts of the stroke research community. For example, at meetings such as the World Stroke Congress (Montreal, 2018) or the European Stroke Organisation Conference (Gothenburg, 2018 and Barcelona, 2016), it was relatively common to hear researchers and doctors claiming from the podium that “… there is no data on this …” or “… there is no evidence for that …”, when they, in fact, meant that the topic lacked data from randomized controlled clinical trials. This is a grave misconception. There is a vast amount of data and solid evidence on, to name a few, the dangers of whole body irradiation, traffic accidents, and starvation, as well as on the benefits of fire brigades, hospitals, and education of health care professionals, in spite of neither of these, to our knowledge, ever being subjected to randomized trials. One could wish to dismiss the misconception of the randomized trial as the sole purveyor of medical evidence as something that will vane, once knowledge both of the limitations of randomized trials and of the advancement of epidemiological research methods that has occurred during the last decades reach all parts of the research community.^5,6 But while we wait for this, however, there is an imminent risk that patients will come to harm, either by being withheld effective treatments or through being included in unwarranted and potentially dangerous randomized trials.

The safety and efficacy of mechanical thrombectomy in the treatment of stroke has been well proven in both observational studies and clinical trials.^7,8 Since the randomized clinical trials included only patients with stroke in the anterior circulation, however, there is still no consensus on how to treat acute basilar occlusion. This is surprising, given that it is known that (1) restoring blood flow after ischemic stroke is equally essential in the posterior circulation as it is in the anterior,⁹ (2) the efficacy of intravenous thrombolysis in restoring blood flow in basilar artery occlusion is low,¹⁰ (3) mechanical thrombectomy is both effective in restoring blood flow as well as safe for the patients,⁸ and (4) there is a vast number of observational studies showing the superiority of mechanical thrombectomy compared to what can be achieved through intravenous thrombolysis alone.^11–13 Surely, there may be call for randomized trials on yet unknown topics such as, for example, proper time windows for treatment or if patients with manifest infarctions at time of presentation should be treated differently, but given the severity of the disease and the poor prognosis for basilar occlusion treated with intravenous thrombolysis only, one would hope that lessons learnt from anterior circulation stroke would prevent such randomized trials on basilar occlusion where one arm is given only treatment that is known to be ineffective. Unfortunately, this is not the case. At present, there are as much as three randomized trials on basilar artery occlusion listed at ClicicalTrials.gov. One of the studies, BEST (NCT02441556), has ended recruiting, but the two other, BASICS (NCT01717755), BAOCHE (NCT02737189), still recruit patients with basilar artery occlusion and randomize these patients to treatment with intravenous thrombolysis only, in spite of the relatively low recanalization rate and poor outcome for this treatment shown in many studies.^10,12,13 With a less biased view of observational studies, such studies would be discarded on ethical grounds. In addition, one may wonder what will be gained from the results. If a null result is found, as was the case for the first randomized trials of thrombectomy in anterior circulation stroke,^14–16 the discrepancy between the evidence from the multitude of observational data and from the majority of randomized trials on anterior circulation stroke, the methods used in the basilar occlusion trial would be put in question, and spark discussions of patient selection and of to what extent the results can be extrapolated to other populations.^17,18 If, on the other hand, the study finds mechanical thrombectomy being significantly better than intravenous thrombolysis, all that will be gained are exact figures, with 95% confidence intervals, on how many patients that were injured by the fact that some in the medical community do not understand, or have emotional bias against, even the best of observational studies. That would be a sad late victory for the tobacco industry.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.