Predictors of thrombolysis in the telestroke and non telestroke settings for hypertensive acute ischemic stroke patients

One major attempt to address the rural-to-urban disparity and expand the availability of best stroke practices is the development of telestroke networks for acute stroke evaluation, management and clinical care [1‐3]. Telestroke technology works to leverage the expertise of the stroke centers to extend the benefits of systemic thrombolysis to rural areas, and to eliminate inequities between rural and urban care of stroke patients. The number of patients receiving rtPA increases by almost a factor of ten over previous numbers when telestroke technology is applied [4, 5]. This is because telestroke extends the expertise of stroke centers to provide enhanced stroke care, particularly the administration of rtPA to smaller rural and community hospitals [6, 7]. Like all medical novelties, it is faster, employs the most recent technology and promotes a better use of limited resources.

Moreover, telestroke technology represents a major growth in many hospitals’ efforts to reduce door-to-needle time [3, 8] outside the traditional role of the telestroke in providing the hub-and-spoke system model for stroke care. Such a centralized role of the telestroke in reducing door-to-needle time may affect treatment times and use of thrombolysis [9‐18]. Whether such a centralized role of the telestroke contributes to the reduction in pretreatment clinical risk factors associated with thrombolysis therapy is not very clear. Irrespective of whether the stroke patient is treated in the telestroke or non telestroke, hypertension is the most influential adjustable variable and the second most powerful clinical risk factor after age for stroke [15, 19‐21]. Hypertensive patients are 60–70% more likely to suffer a stroke when compared to those without hypertension [22‐25]. The strong relationship between stroke and hypertension has been investigated extensively [18, 23, 26‐29]. Findings from these studies result in suggestions for the optimization of various hypertensive medications in hypertensive stroke patients prior to treatment with thrombolysis therapy. High-quality telestroke care remains efficient for all stroke patients [30], and the role of the telestroke is expected to increase with benefits of thrombolysis [31] for stroke patients including those with incidence of hypertension. Past studies have shown that decreases in mean arterial pressure (MAP) have a negative association with cerebral blood flow and patients with chronic hypertension have shifts in perfusion autoregulation parameters as well as changes in collateral blood supplies [32, 33]. This, in conjunction with other considerations such as carotid artery stenosis [34‐36], put hypertensive stroke patients at a unique risk special consideration should be considered when determining rtPA eligibility in these patients.

In general, the association of the telestroke technology and thrombolysis therapy with exclusion or inclusion clinical risk factors in hypertensive stroke is not fully understood. Since stroke with hypertension is dynamic and complicated, one possibility is that the telestroke technology may be less or more stringent in the inclusion or exclusion of clinical risk factors for thrombolysis therapy when compared with the non telestroke setting for hypertensive stroke patients. We hypothesize that the practice-based model of telestroke can manage pretreatment clinical risk factors in hypertensive stroke patients for thrombolysis therapy even in the quest for faster growth and, in so doing telestroke may function as a model to relax the criteria for the inclusion or exclusion for thrombolysis in hypertensive stroke patients.

A total of 434 stroke patients with hypertension were admitted to the non telestroke while 267 were admitted in the telestroke. Comparisons between the baseline demographic and clinical characteristics of telestroke and non-telestroke patients are presented in Table 1. Compared to the non-telestroke control group, telestroke patients were younger (66.1 ± 13.5 vs. 70.1 ± 14.1), included more African-American or other minority group individuals (19.1% vs. 12.2%), and have a higher body mass index (30.8 ± 7.3 vs. 28.2 ± 6.7). Prior to admission, telestroke patients had lower rates of atrial fibrillation or atrial flutter (11.6% vs. 27.2%) and were less likely to have had a previous stroke (24.7% vs. 32.0%), but more likely to have diabetes (46.1% vs. 38.0%), depression (18.0% vs 0.2%), hormone replacement therapy (3%0 vs 0.7%) and more likely to be currently medicated for diabetes (37.1% vs. 27.4%). Initial labs at the time of presentation showed that telestroke patients tended to have lower creatinine (1.2 ± 0.8 vs. 1.4 ± 1.1), lower INR (1.0 ± 0.2 vs. 1.1 ± 0.5), lower heart rate (78.2 ± 15.9 vs. 82.7 ± 18.5), systolic blood pressure (148.3 ± 24 vs 155.9 ± 30.9), and diastolic blood pressure (79.8 ± 16.3 vs. 83.6 ± 20.6). Telestroke patients also had a better ambulatory status prior to admission, at the time of presentation, and at discharge, were more likely to receive rtPA (89.1% vs. 38.7%) and were more likely to experience an improved ambulatory status at discharge relative to presentation (70.4% vs. 58.1%).

Clinical characteristics associated with the inclusion and exclusion for rtPA for patients with a history of hypertension in the telestroke and non-telestroke cohorts are presented in Table 2. Of the 434 that were admitted in the non telestroke 61.3% were excluded from rtPA while 38.7% received rtPA. For the telestroke, 10.9% were excluded while 89.1% hypertensive stroke patients received rtPA. In the non-telestroke, patients who received rtPA were younger than patients who did not receive rtPA (68 ± 14.3 vs. 71.4 ± 13.9). Patients who received rtPA outside of a telestroke network presented with lower rates of carotid artery stenosis (2.4% vs. 7.9%), congestive heart failure (9.5% vs. 16.9%), previous stroke (23.2% vs. 37.6%), prosthetic heart valve (0% vs. 3.4%), renal insufficiency (3.0% vs. 10.5%), and lower blood glucose level (138.6 ± 68.7 vs. 158.9 ± 95.1). Patients treated with rtPA outside of the telestroke network also presented with a lower creatinine (1.2 ± 0.5 vs. 1.5 ± 1.4), and INR (1.1 ± 0.1 vs. 1.2 ± 0.6). Patients who received rtPA were more likely to experience improvement in their ambulatory status from presentation to discharge (65.5% vs. 53.4%). Within the telestroke subgroup there were fewer statistically significant differences between patients who received rtPA and patients who were excluded from rtPA. Patients who received rtPA were more likely to have a family history of stroke (13.4% vs 0%).

Following the use of multivariate analysis to adjust for the cofounding effects of comorbidities in the telestroke and non-telestroke (Table 3), patients that present with obesity (OR = 2.351, 95% CI, 1.352–4.087, P = 0.002) were directly admitted for treatment (OR = 32.855, 95% CI, 15.706–68.727, P < 0.001) and received rtPA (OR = 5.199, 95% CI, 2.647–10.211, P < 0.001) have higher odds of being associated with the telestroke, while higher systolic blood pressure (OR = 0.987, 95% CI, 0.977–0.997, P = 0.01) was associated with the non telestroke. The Receiver Operating Characteristics (ROC) curve for the predictive power of the regression model is presented in Fig. 1. The discriminating capability of the model was very good as shown by the ROC curve, with area under the curve (AUROC) of 0.900 (95% CI, 0.875–0.924, P < 0.001). Further adjusted analysis was performed focusing on the whole stroke population (Table 4). This analysis determined clinical and demographic factors that were associated with inclusion for rtPA, irrespective of whether patients were treated in the telestroke or non telestroke setting. The results indicate that telestroke as a variable was the strongest predictor of rtPA administration (OR = 5.204, 95% CI, 2.582–10.492, P < 0.001), followed by a direct admission (OR = 4.557, 95% CI, 1.772–11.721, P = 0.002), and higher NIH stroke scale score (OR = 1.046, 95% CI, 1.016–1.076, P = 0.002). A higher INR, (OR = 0.203, 95% CI, 0.06–0.691, P = 0.011), history of previous stroke (OR = 0.476, 95% CI, 0.293–0.775, P = 0.003), and renal insufficiency, (OR = 0.351, 95% CI, 0.143–0.858, P = 0.022), were predictive of exclusion of stroke patients with hypertension from rtPA. As shown in Fig. 2, the predictive power of the logistic regression was strong. The area under the curve (AUROC) is 0.792 (95% CI, 0.753–0.830, P < 0.05).

In the non-telestroke subgroup (Table 5), higher NIH stroke scale score (OR = 1.059, 95% CI, 1.025–1.093, P < 0.001) and history of coronary artery disease (OR = 2.003, 955 CI, 1.16–3.457, P = 0.013) were associated with rtPA administration while increasing age (OR = 0.979, 95% CI, 0.961–0.996, P = 0.017), higher INR (OR = 0.146, 95% CI, 0.032–0.665, P = 0.013), history of previous stroke (OR = 0.39, 95% CI, 0.223–0.68, P = 0.001), and renal insufficiency (OR = 0.153, 95% CI, 0.046–0.508, P = 0.002) are associated with rtPA exclusion. The ROC curve reveals a strong prediction of the logistic regression model (Fig. 3), AUROC = 0.650 (95% CI, 0.602–0.699, P < 0.005). An adjusted analysis for the telestroke subgroup (Table 6), reveals that only direct admission is associated with rtPA administration, (OR = 4.083, 95% CI, 1.322–12.611, P = 0.014), and the predictive model power of the logistic regression was strong (Fig. 4), AUROC = 0.678 (95% CI, 0.639–0.718, P < 0.05).

In a population of hypertensive stroke patients, we found patients that present with obesity, who are directly admitted to the hospital, and received rtPA have higher odds of being associated with the telestroke, while those with a higher systolic blood pressure were associated with the non telestroke. After adjusting for comorbidities without sorting by telestroke and non telestroke, we found that irrespective of whether patients were treated in the telestroke or non telestroke, the telestroke represents the strongest predictor of rtPA administration followed by a direct admission and NIH stroke scale scores. However, a higher INR, history of previous stroke and renal insufficiency were predictors of exclusion of hypertensive stroke patients from rtPA.

In the univariate analysis for the non telestroke, a higher NIH stroke scale score and history of coronary artery disease were associated with inclusion for rtPA while increasing age, higher INR, history of previous stroke, and renal insufficiency were all associated with rtPA exclusion. Following an adjustment for the baseline clinical variables in the telestroke subgroup, direct admission was the only factor associated with rtPA administration with a strong predictive power in the regression model. Clearly, the higher proportion of clinical risk factors associated with exclusion in the non telestroke when compared with the telestroke is not unconnected with the exclusion of more hypertensive stroke patients from rtPA; because though the non telestroke admitted more patients (62% vs 38%) when compared with the telestroke, more patients (61.3% vs 38.7%) were excluded from rtPA. We observed that the telestroke admitted fewer patients, excluded 11% and administered thrombolysis therapy to 89% of hypertensive stroke patients. It is possible that the telestroke technology provides a real-world clinical experience with less stringent or restrictive exclusion criteria focused more on benefit-to-risk ratio for thrombolysis therapy. The fact that the non telestroke group had more clinical risk factors associated with exclusion from thrombolysis indicates that stricter criteria were used when compared with the telestroke group, which had less stringent criteria on an individual basis. In a whole stroke hypertensive population telestroke was the strongest predictor of rtPA administration, followed by a direct admission and higher NIH stroke scale score respectively. Our model predicted a direct association of telestroke with the highest odds for the inclusion of hypertensive stroke patients for thrombolysis therapy. Other studies have indirectly linked the telestroke technology with the improvement of stroke care in rural health care centers [13], increased rate of rtPA administration [38, 43] and improvement of the timeliness of rtPA administration [39, 40]. Our finding of a strong association of telestroke with thrombolysis may reflect the fast response for the early recommendation of administration of rtPA in the hub station and faster administration in the spoke station resulting in significant increases in the rates of rtPA utilization at the spoke hospitals. There is a growing evidence that telemedicine services offer hypertensive patients the access to diagnostic measures [41, 44] that might not be available with usual bedside evaluation care. This indicates that telemedicine has the ability to deconstruct the typical traditional model in the standard clinical consultation [29]. This might impact the management of hypertension in ischemic stroke beyond the use of antiHTN in the telestroke with some form of additional support compared with usual care not common in the non telestroke. In this context, the telestroke could be a part of the solution to improve the rate of thrombolysis in hypertensive stroke patients.

In the univariate analysis, the effect of direct admission was not significant in both the telestroke and non telestroke settings. Following an adjusted analysis for both the telestroke and non telestroke, a direct admission of patients was associated with thrombolysis in the telestroke setting. The significant association of direct admission with thrombolysis was sustained in the whole stroke population following adjustment for baseline demographic and clinical risk factors. In general, direct admission is known to be associated with shorter onset-to-needle time and better outcome in patients with acute ischemic stroke undergoing thrombolysis [45‐50]. This is because a direct admission to the telestroke could reduce the door-to-needle time for thrombolysis to within an hour in more than 70% of acute ischemic stroke patients and less than 50 min in more than 45% of stroke patients [51‐53]. Many methods have been proposed to reduce door-to-needle time for thrombolysis, including in-hospital system-level centralized telestroke care [10, 13, 16, 54‐58]. Therefore, it is possible that in hypertensive stroke patients, telestroke may be associated with improved thrombolysis therapy use by facilitating a direct admission that improves the time to receive thrombolysis therapy. Such a time improvement could be due to the reduction of the time between hub stroke neurologist’s and spoke clinician’s involvement in the management, treatment, and implementation of the protocol to mix rtPA and administer thrombolysis to hypertensive stroke patients.

Our finding that INR, previous stroke and increased age (> 80 years) are associated with exclusion of hypertensive stroke patients from rtPA have been reported as exclusion variables in acute ischemic stroke patients [3, 59‐66]. In general, existing guidelines regarding INR results are intended to prevent hemorrhages and, specifically intracranial hemorrhage which is the most dreaded complication of rtPA in patients taking oral anticoagulants. In particular, the AHA/ASO guidelines [67] recommend that, the administration of rtPA can be initiated before results of coagulation tests or platelet counts are available, unless a bleeding is observed after the patient had already received heparin or other anticoagulants. However, if rtPA protocol has been initiated and the results of the coagulation tests or platelet counts indicate that INR > 1.7 or a PT > 15 s by local protocol of rtPA administration, then the procedure should be stopped [68]. This might have contributed to the exclusion of more patients in the non telestroke in our current study.

We found that hypertensive stroke patients with age > 80 years are more likely to be excluded more from rtPA in the non telestroke setting. Observational studies aimed at monitoring the safety of rtPA provided comparative results on stroke outcome between patients > 80 years and those < 80 years [63, 69‐72]. Findings reveal that > 80 years are less likely to achieve good outcomes compared with < 80 years. Most of the observational studies evaluated age differences between older and younger patients receiving rtPA. In our adjusted analysis, more hypertensive stroke patients > 80 years are more likely to be excluded from rtPA compared with > 80 years that received rtPA in the non telestroke. In general, patients with an elevated INR and a previous stroke within the last 3 months are associated with contraindications for rtPA in other studies [38, 64, 73‐77]. Therefore, the combined effect of old age coupled with elevated INR and a previous stroke within the last 3 months played a role in the exclusion criteria in acute ischemic stroke patients with incidence hypertension in the current study.

There are limitations in this study. This is a single healthcare system initiative with retrospective data collection. Therefore, there is the tendency for selection bias because of the lack of an experimental design that allows for randomization, especially at telestroke or non telestroke settings. For this reason, our finding cannot be generalized to other hospital settings. Since our data is pretreatment, and post treatment only until discharge from the hospital, it did not include longitudinal data for a follow-up to determine the effect of direct admission on post rtPA outcome. Moreover, information about the management of hypertension and the time for direct and indirect admission was not included in our analysis, preventing comparison of onset-to-door time between indirect and direct admission. The number ischemic stroke patients that needed antihypertensive treatment before rtPA were not included. However, our model associated telestroke with thrombolysis in providing clinical practice with less restrictive exclusions focused more on benefit-to-risk ratio for thrombolysis therapy in stroke patients with hypertension.

In summary, telestroke was the strongest predictor of rtPA administration, followed by a direct admission and higher NIH stroke scale score. More studies are necessary to determine how identified exclusion risk factors in the non telestroke setting can be improved, including a direct transfer of hypertensive stroke patients to health care centers with a direct access to thrombolysis.