Determinants of Exclusion from Treatment with Alteplase in Acute Ischemic Stroke at the Largest Tertiary Center in Lebanon

  


    
Patient-related    factors

    
TPY (n=40)

    
TPN (n=25)

    
p-value

  

  


    
Male gender

    
24 (60%)

    
12 (48%)

    
0.344

  

  


    
Median age    (range)

    
72 (36-94)

    
86 (36-100)

    
0.018

  

  


    
Median time    since symptom onset in hours (range)

    
1.5 (0.4-4)

    
2 (0.5-4)

    
0.218

  

  


    
Median NIHSS    (range)

    
11.5 (6-31)

    
7 (6-22)

    
0.032

  

  


    
Presenting    symptoms

  

  


    
Common symptoms

    
5 (12.5%)

    
4 (16%)

    
0.691

  

  


    
Uncommon    symptoms

    
35 (87.5%)

    
21 (84%)

    


  

  


    
Anti-platelet

    
9 (22.5%)

    
14 (56%)

    
0.021

  

  


    
Type of stroke

  

  


    
TACI

    
15 (37.5%)

    
7 (28%)

    
0.774

  

  


    
PACI

    
19 (47.5%)

    
12 (48%)

    


  

  


    
POCI

    
2 (5%)

    
1 (4%)

    


  

  


    
LACI

    
3 (7.5%)

    
3 (12%)

    


  

  


    
Multiple    territories

    
1 (2.5%)

    
2 (8%)

    


  

  


    
Logistic factors

    


    


    


  

  


    
Method of    transportation to ED

  

  


    
Ambulance

    
18 (51.4%)

    
8 (34.8%)

    
0.212

  

  


    
Other means

    
17 (48.6%)

    
15 (65.2%)

    


  

  


    
ED factors

  

  


    
Code activation

    
27 (79.4%)

    
9 (40.9%)

    
0.011

  

  


    
Median time from    arrival to CT (range)

    
21 (1-45)

    
24 (1-122)

    
0.2

  

Table 2: Bivariate analyses of patient-related and logistic variables.

Multivariate analysis: After performing multivariate logistic regression, three variables were statistically associated with corresponding to the TP. For every point increase in the NIHSS, there was 22% higher odds of being in the TP (OR 1.22 (1.14-1.31), P<0.0001). TACI and PACI stroke subtypes had higher odds of corresponding to the TP than the NTP (OR 3.58 (1.49-8.6), p=0.004), and a longer duration since symptom onset (in hours) was associated with corresponding to the the NTP (OR 0.14 (0.07-0.27, p<0.0001).

Target Patients Having Taken or Not rTPA (TPY vs TPN)

Patient-related factors: In patients who were candidate for IV rTPA administration with no absolute or relative contraindications, we looked at possible risk factors that could be associated with having received or not rTPA. Gender distribution was similar between TPY and TPN groups, but patients who received rTPA were younger. The mean time since symptom onset did not differ between both groups, but mean NIHSS was higher in TPY. Both groups had similar frequencies of common and uncommon symptoms, and the type of stroke did not differ between them. More patients who did not receive rTPA were on single or dual anti-platelets. New hypodensities on brain Computed Tomography (CT) were more commonly seen in patients who were not treated with rTPA, however, having a hyperdense Middle Cerebral Artery (MCA) sign was not associated with having received rTPA.

Logistic factors: No difference was seen in the method of transportation (ambulance or other means), the month, day of presentation and time of arrival to ED between TPY and TPN groups.

ED factors: The neurology resident’s post-graduate level and gender did not differ between having received rTPA or not, as well as the mean years since graduation of the attending neurologist overseeing the case. Nevertheless, the stroke code was more commonly activated in the TPY group.

Multivariate analysis: Three variables showed statistically significant associations with having received rTPA or having been excluded from treatment in the multivariate analysis. The older the patient’s age, the lower his chances of receiving rTPA (OR 0.95 (0.91- 0.99), p=0.029). Stroke code activation was strongly associated with TPY (OR 2.81 (1.16-6.81), p=0.022) and the higher the patients’ NIHSS at presentation, the higher their odds of being treated with rTPA (OR 1.12 (1.01-1.25), p=0.041).

Discussion

Despite the progressively-increasing rate of rTPA administration reported by prior studies, a large number of patients with acute ischemic stroke does not fit the criteria to receive it, and up to 20% of potentially eligible patients do not get treated [5]. This retrospective analysis of stroke patients presenting to the biggest tertiary center in Lebanon sheds light on some patient-related and logistic factors thatare associated with not being eligible for rTPA administration and not receiving it when eligible.

The main absolute contraindication excluding patients from rTPA treatment was arriving to the ED after more than 4.5 hours since last seen normal. In fact, the longer the duration was since symptom onset, the lower the chances were of being eligible to treatment. Intravenous thrombolysis was initially proven to be successful in the first 3 hours since symptom onset in the NINDS trial in 1995 [1], and the window was then extended up to 4.5 hours based on the ECASS III trial published in 2008 [6]. Recently, rTPA was proven to improve the functional outcome at 90 days in patients with AIS presenting beyond 4.5 hours from symptom onset or with an unknown last-seen well or wake-up stroke, given they had Diffusion-Weighted Image (DWI)/ Fluid-Attenuated Inversion Recovery (FLAIR) mismatch on brain Magnetic Resonance Imaging (MRI) [7]. However, this new concept was not applied in our study since data collection stopped by the time the trial results were published.

Another factor associated with not being candidate for rTPA is the type of stroke. Having Posterior Circulation (PC) ischemia or a lacunar stroke were associated with a higher risk of not being eligible for rTPA. PC ischemiadoes not present with classical stroke symptoms, and the relatively rich collateral system render the clinical symptoms highly variable [8]. Nonspecific manifestations such as dizziness, imbalance, slurred speech, headache, nausea, and vomiting, could constitute the initial presentation of PC strokes, making their recognition by ED physicians and even neurologists hard [9]. Furthermore, decision-making heavily relies on the NIHSS, which reflects stroke severity. However, this scale has limitations in posterior circulation ischemia, where fewer points are attributed to cranial nerve deficits and ataxia, while higher points are assigned to anterior circulation stroke [8]. This could possibly explain why patients with PC stroke are less eligible to receive rTPA and end up with less favorable functional outcomes at 3 months. On the other hand, lacunar strokes are small sub cortical infarcts located in the deep structures such as the brainstem, thalamus, basal ganglia, internal capsule and corona radiate [10]. Their manifestations consist of typical lacunar syndromes such as pure motor or sensory deficits, sensorimotor stroke, dysarthria-clumsy-hand syndrome or ataxic hemiparesis. Those symptoms frequently do not cross the NIHSS threshold for giving rTPA and this category of strokes might be considered as the most benign subtype, which could explain why these patients are usually less eligible for treatment [10].

A lower NIHSS not only renders acute ischemic stroke patients less eligible for rTPA but is also associated with less frequent treatment in those who are candidate. The most recent guidelines from the American Heart Association/American Stroke Association for early management of patients with acute ischemic stroke state that an eligible patient should have an NIHSS between 6 and 25, except those with minor (NIHSS<6) but functionally-impairing symptoms [11]. Thus, this study contributes to the reporting of prespecified contraindications excluding patients from treatment. Unfortunately, we did not categorize minor symptoms into functionally and non-functionally-impairing deficits to analyze the rate of rTPA administration in these sub-categories. Furthermore, in patients who are eligible and have no contraindications, lower NIHSS was strongly associated with a lower likelihood of receiving rTPA. This was found to be the most common cause for not treating otherwise candidate patients, though numerous studies reported poor long-term prognosis even with mild untreated stroke symptoms [12]. Despite excluding those patients from older rTPA trials, a recent post hoc analysis of mild acute ischemic stroke patients from the International Stroke Trial 3 (IST3) randomized controlled trial and multiple metaanalyses proved the efficacy of rTPA in this sub-population, especially if treated within 3 hours of onset [13,14].

One of the relative contraindications in patients presenting within 3 and 4.5 hours from symptom-onset, is age above 80 years. Our study showed that even in eligible patients presenting with neither absolute nor relative contraindications, the older they are, the less likely they are to receive rTPA treatment. Multiple meta-analyses and the IST3 have recently demonstrated sustained improved outcomes after thrombolysis in the elderly and even in the very elderly [15,16]. However, a recent survey of neurologists showed that 4 out of 5 were less encouraged to give rTPA in elderly patients, especially those coming from nursing homes or those more than 80 years of age [17]. This could be explained by the fear of inducing intracerebral or systemic bleeding in this fragile population [18].

Among eligible patients, stroke code activation was more common is those who received treatment with rTPA compared to those who did not. In the emergency department, stroke code activation heavily relies on the fast recognition of stroke symptoms by ED nurses, medical students, residents and fellows. It entails a rapid arrival of the neurology team with the goal of recanalization and reperfusion, as well as a fast sequence of imaging and laboratory testing. Hence, stroke code activation results in reduction of in-hospital delays [19], which is why it is crucial to train the ED staff for an accurate and safe identification of stroke manifestations.

Multiple independent factors were also associated with not being a target patient; one of which was having uncommon stroke symptoms. Manifestations such as headache, dysarthria, dizziness, gait instability, and altered behavior are non-specific and can occur in a variety of neurological illnesses, rendering them less recognizable as stroke symptoms [20]. In fact, stroke code activation with common symptoms was independently more associated with being a target patient in our study. In addition, arriving to the hospital via ambulance and a shorter time from ED arrival to brain CT acquisition, were associated with being a candidate for rTPA. However, that could partially be mediated by more recognizable stroke symptoms and stroke code activation [21,22].

Being on anti-platelet treatment (single or dual) was independently associated with not receiving rTPA in otherwise eligible patients. Although blood thinners may be thought to increase the risk of symptomatic intracerebral hemorrhage (sICH) after rTPA in patients with AIS, a study on 11,865 patients showed that the absolute excess of sICH in patients on anti-platelets is very small compared with the advantages of thrombolysis [23]. Caution is needed in patients taking dual anti-platelets, especially if they are older and have severe white matter disease, but treatment with anti-platelet should not be considered a contra-indication to rTPA administration.

There are several limitations to this study. First, this is a retrospective chart-review study, which limits our access to some information like comorbidities, time intervals (e.g. neurologist arrival and time from arrival to brain CT), and reasons behind not receiving rTPA, especially in candidate patients. This might mask the existence of important non-documented factors associated with exclusion from treatment. Furthermore, we defined eligible patients as those presenting within 4.5 hours from symptom onset, knowing that patients with AIS can still be eligible based on specific MRI findings even if their last-seen well was unknown. In addition, we focused on factors related to exclusion from thrombolysis, but not on those associated with treatment delays. Finally, we did not control for baseline dementia and disability in the study sample, or other variables that might have played a role in discouraging the neurologist to treat with rTPA certain patients, and many of these reasons were not documented in the charts.

In conclusion, a proportion of patients with AIS were excluded from rTPA treatment. Posterior circulation or lacunar strokes and a longer time since symptom onset render the patients less eligible to treatment, while an older age and no stroke code activation as was associated with exclusion from treatment. Lower NIHSS scores were associated with treatment exclusion, regardless if the patient was a candidate or not. In order to improve the rate of rTPA administration, public health efforts should be exerted to educate the public about the typical and atypical stroke symptoms and the need to be transported by an ambulance, if stroke is suspected. Logistic factors related to access to the hospital and routing like helicopters and shortcuts are also important .Moreover, the ED staff must also be thoroughly trained to activate stroke codes whenever appropriate, in order to increase the chances of patients being treated.

References

1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995; 333: 1581-7.
2. Lahr MMH, Luijckx GJ, Van der Zee DJ, Buskens E. Proportion of Patients Treated With Thrombolysis in a Centralized Versus a Decentralized Acute Stroke Care Setting. Stroke. 2012; 43: 1336-40.
3. Barber PA, Zhang J, Demchuk AM, Buchan A. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology. 2001; 56: 1015-20.
4. Kleindorfer D, Kissela B, Scheinder A, Woo D, Khoury J, Miller R, et al. Eligibility for recombinant tissue plasminogen activator in acute ischemic stroke: a population-based study. Stroke. 2004; 35: e27-9.
5. Messé SR, Khatri P, Reeves M, Smith E, Saver JL, Bhatt DL, et al. Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry. Neurology. 2016; 87: 1565-1574.
6. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetto D, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359: 1317-29.
7. Thomalla G, Simonsen CZ, Boutitie F, Andersen G, Berthezene Y, Cheng B, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018; 379: 611-622.
8. Nouh A, Remke J, Ruland S. Ischemic posterior circulation stroke: a review of anatomy, clinical presentations, diagnosis, and current management. Frontiers in neurology. 2014: 5: 30-30.
9. Dorňák T, Král M, Šaňák D, Kaňovský P. Intravenous Thrombolysis in Posterior Circulation Stroke. Frontiers in neurology. 2019; 10: 417-417.
10. Pantoni L, Fierini F, Poggesi A. Thrombolysis in acute stroke patients with cerebral small vessel disease. Cerebrovasc Dis. 2014; 37: 5-13.
11. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019; 50: e344-e418.
12. Khatri P, Conaway MR, Johnston KC. Ninety-day outcome rates of a prospective cohort of consecutive patients with mild ischemic stroke. Stroke. 2012; 43: 560-2.
13. Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012; 379: 2352-63.
14. Khatri P, Tayama D, Cohen G, Lindley R, Wardlaw JM, Yeatts SD, et al. Effect of Intravenous Recombinant Tissue-Type Plasminogen Activator in Patients With Mild Stroke in the Third International Stroke Trial-3: Post Hoc Analysis. Stroke. 2015; 46: 2325-7.
15. Mishra NK, Diener HC, Lyden PD, Bluhmki E, Lees KR. Influence of age on outcome from thrombolysis in acute stroke: a controlled comparison in patients from the Virtual International Stroke Trials Archive (VISTA). Stroke. 2010; 41: 2840-8.
16. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014; 384: 1929-35.
17. Shamy MC, Jaigobin CS. The complexities of acute stroke decision-making: a survey of neurologists. Neurology. 2013; 81: 1130-3.
18. Alshekhlee A, Mohammadi A, Mehta S, Edgell RC, Vora N, Feen E, et al. Is thrombolysis safe in the elderly?: analysis of a national database. Stroke. 2010; 41: 2259-64.
19. Hsiao CL, Su YC, Yang FY, Liu CY, Chiang HL, Chen GC, et al. Impact of code stroke on thrombolytic therapy in patients with acute ischemic stroke at a secondary referral hospital in Taiwan. J Chin Med Assoc. 2018; 81: 942- 948.
20. Newman-Toker DE, Moy E, Valente E, Coffey R, Hines AL. Missed diagnosis of stroke in the emergency department: a cross-sectional analysis of a large population-based sample. Diagnosis. 2014; 1: 155-166.
21. Xu H, Xian Y, Woon FP, Bettger JP, Laskowitz DT, Ng YY, et al. Emergency medical services use and its association with acute ischaemic stroke evaluation and treatment in Singapore. Stroke and vascular neurology. 2020; 5: 121-127.
22. Barbour V, Thakore S. Improving door to CT scanner times for potential stroke thrombolysis candidates - The Emergency Department’s role. BMJ quality improvement reports. 2017; 6: u211470.w4623.
23. Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ, et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients receiving antiplatelet therapy at stroke onset. Stroke. 2010; 41: 288-94.