This sub study in PASS, a large Dutch stroke with acute stroke patients, showed an up-to-date prevalence of CAS in patients with AIS of 18.7% with age, hypertension, male gender and smoking identified as predicting factors for the presence of ICA stenosis. This prevalence is in line with published research, as well as the found predictors for ICA stenosis.(2–6) Ordinal regression analysis showed an adjusted common OR of 1.66 for ICA stenosis for a worse outcome after stroke in patients who also have CAS. Dichotomized, the mRS showed a worse functional outcome in these patients as well, both in mortality and in less patients in the group with good functional outcome (mRS 0–2). An ICA stenosis ≥ 50% as a predictor for worse functional outcome after stroke is a new finding and has not been reported before.
Even though the prevalence that was found is in line with the previous reports on prevalence of CAS in AIS, it is higher than we expected. While in the last decade major improvements have been made in reducing CVD risk factors, some of which we specifically found as predictors for presence of CAS, it had no effect on the shown prevalence of CAS in this sub study. In 2007 Ford et al. reported that the decrease in deaths from coronary disease and they attributed 44% of the decrease to improvement of CVD risk factors. Mostly caused by the lowering of systolic blood pressure, reduction in percentage of smokers and lowering of blood cholesterol.(9) Furthermore, it has been reported that the overall diet in the population have become healthier and people have accustomed a less sedentary life-style.(10–12) Considerable differences in change of risk factors have been described between countries and continents with potentially a less healthy food pattern in developing countries. Overall, CVD remain the most important cause of death worldwide. Even though western countries did see decreasing numbers of CVD death, with a sharper decrease in coronary death compared to stroke mortality, while developing countries saw an increase in both complications.(13) The fact that in these recent data we did not find a lower prevalence of CAS, as marker of large-vessel disease, remains surprising.
An important consideration is that the formation of carotid atherosclerosis and stroke as final effect take a substantial amount of time to develop. The patients that finally suffer from a stroke as a result of CAS are probably the patients with most comorbidities in the CAS group. It can be expected that this group will need far more reduction of risk factors in the general population to reverse CAS in these patients, if it is possible to reverse CAS at all. The majority of patients with CAS that we included in this study, could have been established before the reduction of risk factors was started, as the formation of atherosclerosis takes multiple decades.
Another explanation could be that the decrease in risk factors is not of a sufficient significance or that other (unknown) risk factors become more important if you look at the overall effects after the reduction of the known risk factors. Taking these factors into account, one could hypothesize that it could take a longer time to find the decreasing prevalence of CAS caused by the measures decreasing CVD risk factors and CAS predictors.
The major strength of this study is the large number of AIS patients with complete follow-up that was used in this sub study. The most important limitation is that patients with TIA were excluded and that in a large number of patients (24.1% of the initial 1951 patients), it is unclear why the information regarding the status of CAS is lacking. This could cause an overestimation of the prevalence of CAS. A possible reason for missing this information is AF as cause of stroke. In these patients, the degree of stenosis of the carotid artery is often not investigated. Furthermore, octogenarians or patients with poor mRs or comorbidities, such as dementia, are often not eligible for revascularization and consequently are not investigated by imaging.
The worse functional outcome of patients with CAS is an interesting finding, even though PASS was not powered to show this difference, which deserves further attention. The general functioning of CAS patients and their overall high CVD risk could be an explanation for the worse outcome in these patients and thus making CAS a symptom of the worse outcome and not necessarily the cause of the worse outcome itself. Furthermore, CAS could be caused by the low-socio economic status that is correlated with most CVD risk factors that were found and are linked to worse outcome overall.(14)
Another explanation for the worse functional outcome could be the chronic inflammatory activity in the local carotid plaque. The specific role of the inflammatory reaction in the vessel wall remains unclear, but it could be a causative factor in more CVD complications. Since in several auto-immune diseases, patients suffer CVD more frequently and lower life-expectancy is seen in these patients.(15, 16) How this elevated CVD cases can be explained is still unknown, but it cannot be described by the traditional CVD risk factors alone. Whether treating the inflammatory reaction is beneficial for CAS patients should be elucidated and CONVINCE will be the first study in neurology focussing on that research question. In this randomized study low-dose colchicine is used as additive to standard secondary prophylaxis in non-cardio embolic stroke patients.(17)