Real-World Effectiveness of Intravenous Stroke Thrombolysis is more than the Expectation of Practicing Neurologists

INTRODUCTION

The global burden of acute ischemic stroke (AIS) is on a rise,[1] and the treatment with intravenous thrombolytic therapy (IVTT) using alteplase within the window period is the most effective and established immediate management strategy of this pandemic.[2] However, despite active efforts from many corners, the thrombolysis rates are still low, especially in the developing world.[23] Although the barriers for thrombolysis are many,[45] low acceptance among physicians may be an important factor.[6] Over-projected bleeding risk and subjective feel of futility[7] may be significant in this regard.[6] The clinical decision-making about IVTT varies among physicians.[78] The negative role of previous bad patient outcome in subsequent decision-making is well established.[9] In practice, most physicians remember a few patients who had no improvement (NI) or worsened following an IVTT. How far this subjective feeling of practicing physicians is substantial? We aimed to survey neurologists in Thrissur city routinely doing IVTT about their subjective feeling of effectiveness of IVTT and compare it with objective results of IVTT in a prospective hospital-based registry.

METHODS

The study was done in Thrissur metropolitan region in the central part of Kerala, South India. The region caters to a population of 1.8 million.[10] Only neurologists in tertiary care hospitals practice IVTT in the region. There were two parts for the study. The first part was to survey the neurologists giving IVTT in the region about their personal opinion on the results of the intervention. The second part was to compare this with the actual clinical outcome of IVTT in a prospective thrombolysis registry maintained in a tertiary care hospital from the same region. Table 1 shows the questions asked in the telephonic survey. Neurologists from institutions with registry data were asked to give their expert opinion but not their data.

Table 1 Questions asked to neurologists in practice during the telephonic survey

The second part of the study was done in a 350-bedded tertiary care hospital in Thrissur metropolitan region. A prospective stroke thrombolysis registry is maintained in the institution with all the clinical details of the cases undergoing IVTT. There are two neurologists in the hospital routinely doing thrombolytic therapy for ischemic stroke patients. Standard protocols are followed for the selection, drug administration, and post-thrombolysis care.[11]

Consecutive cases of ischemic stroke from April 2012 to March 2016 in the thrombolysis registry were selected for the analysis. The registry data were verified by reviewing the charts of all cases. Notice was made on demographic data, time delay in reaching the emergency room (ER), door-to-needle time, and the type of ischemic stroke. Risk factors, comorbidities, current drug usage, blood glucose, and blood pressure (BP) at presentation and complications during hospital stay were also noted. National Institute of Health Stroke Scale (NIHSS) scores[12] recorded at presentation to ER, at 24 h, at 7 days, and at 30 days or at the time of discharge were noted. Modified Rankin Scale (mRS) scores[13] before the stroke, at 24 h, at 7 days, and at 30 days or at the time of discharges were similarly noted. Furthermore, Alberta Stroke Program Early Computerized Tomography Scores (ASPECTS)[14] at presentation to ER and at 24 h were noted. The benefit of IVTT was categorized into four types [Table 2].

Table 2 Categorization of the benefits of intravenous thrombolytic therapy

RESULTS

DISCUSSION

Despite the striking benefit of IVTT in AIS, its use is limited to a minority of stroke patients in India and rest of the world, other than big academic stroke centers.[23] Although various reasons have been put forward for this discrepancy, authors have come across another curious reason during the discussions with fellow neurologists from institutions with less number of IVTT per year. Many subjectively felt that the benefit, if at all, with IVTT is modest and bleeding risk is high.[567] They do remember cases in which they landed in trouble. We thought that this feeling of the treating neurologists might be another reason for the low IVTT rates. How far this subjective feeling of futility about IVTT is substantial?

We wanted to compare the subjective feeling of benefit and complications of IVTT with objective measure of the same. For this comparison, we selected a group of practicing neurologists in a metropolitan region and assessed their subjective feeling about IVTT by a structured questionnaire. These data were compared with the objective results of the IVTT in a thrombolysis registry of a hospital from the same metropolitan region. We postulated that the subjective feeling of futility of IVTT might be a reason for lower thrombolysis rates.

Overall, the survey among practicing neurologists has shown that the bleeding risk of IVTT, which they think, is around 10%. They feel that roughly only a third really benefitted from IVTT, whereas another third have no benefit or worsening due to IVTT and the remaining third has a slow natural recovery not related to the drug effect. However, our results in the thrombolysis registry were not supporting this. Although the ICH rate was around 10%, GSB was seen in 49% at 7 days of IVTT and a good functional outcome (mRS 0–2) of 57.3% at the time of discharge from hospital or at 30 days of stroke. The rate of bad outcome (NI or worsening) of 36% was similar to what was anticipated by the neurologists in the survey. These higher than anticipated GSB at 7 days and functional outcome at the time of discharge/at 30days were present in posterior circulation and cardio-embolic strokes as well.

Another important observation is that the rates of slow “natural recovery,” which the practicing neurologists “predicted,” are not correct. Only 13% had this course, and in fact, even these people had significant recovery at 7 days. This is the reason why there is 57.3% good functional outcome at 30 days or at discharge. Hence, this group also has to be taken as those who are having good benefit to IVTT (and not as “unrelated natural recovery”).

Thus, the registry shows that around 60% of people receiving IVTT have a good outcome at the time of discharge or at 30 days. This is certainly in contrast to the one-third good outcome anticipated by practicing neurologists. The anticipated low outcome may be influencing the thrombolysis decisions and the rates of low thrombolysis.[78] Why does this discrepancy occur. We feel that it is related to the memory about really bad cases, which the physician had treated in the past. He may not be remembering the chunk of good cases he had treated. A similar scenario in aortic aneurysm surgery is detailed elsewhere.[9] Our study is really an eye-opener, which advises the physician that subjective feeling may not be correct and the actual data are more important. Analysis of our registry correlate well with large series.[15] Compared to the neurologists in the survey who used to stick to the time window, we even had gone out of the window period, treating wake-up strokes.[16] Still our patients had good outcome compared to what is anticipated by those in the survey, once again underscoring the benefit of IVTT.

The rate of ICH related to IVTT in our series is higher than the recent registries.[31517] The reason may be that we included at least a few cases outside the window period. However, in the survey also, neurologists felt roughly 10% ICH rates. Whether IVTT-related ICH rates are really high in our population? Although there is a suggestion in a recent study,[18] this requires further investigation.

CONCLUSION

The IVTT in AIS has a very good functional outcome, contrary to the belief of neurologists practicing the therapy. We believe that the therapeutic nihilism related to the apprehension of practicing neurologists about the benefit of IVTT is a strong reason for low thrombolysis rates, at least in our part of the world. Keeping registries in every institutions and periodically reviewing the data could mitigate this.