Study Design

Following the STROBE guideline⁸, it is a retrospective observational unmatched case-control study.

Study Location and Period

The current study was carried out at the Hospital Regional do Cariri by verifying data registered in the medical records of patient’s victims of ICVA who underwent intravenous thrombolysis therapy from January 2014 to December 2017.

Study Population and Eligibility Criteria

It consists of patients treated at the HRC, diagnosed with ICVA, who underwent intravenous thrombolytic therapy and monitored daily through the NIHSS protocol in the Stroke Unit at HRC. The HRC has approximately 100 CVA admissions monthly. The researchers checked all medical records of patients admitted during the study period.

The study included participants over eighteen years old with the clinical diagnosis of ICVA who presented a neurological deficit of significant intensity with an evolution time less than 4.5 hours before the start of thrombolytic infusion and cranial tomography without evidence of bleeding for its use, characterizing such as incident cases of ICVA. On the other hand, for both groups (case and controls) the medical records with incomplete data that could affect the interpretation of essential data for this study were excluded to reduce information bias.

Participants who did not show a reduction in the NIHSS score after using the thrombolytic therapy were defined as cases, while controls were those who showed a reduction in the NIHSS score and improved symptoms, resulting in an unmatched control group.

Data Collection

All variables were collected from medical records filed at the HRC of patients clinically diagnosed with ICVA who underwent intravenous thrombolytic therapy.

Gender, age, smoking, diabetes, and hypertension were related to the participants’ sociodemographic characteristics and history. Variables at the time of admission were collected to investigate whether any aspect between blood pressure and blood glucose levels and NIHSS score is related to non-reduction in the NIHSS score. The presence of cranial computed tomography findings related to ischemia, time from stroke to thrombolysis, and post-thrombolysis hemorrhagic transformation.

Some quantitative variables were categorized according to the cutoff points presented in box 1.

Data Analysis

Descriptive statistics were presented using absolute and relative frequencies and odds ratio. The logistic regression was used to investigate the factors related to the risk of not showing a reduction in the NIHSS score between the groups. We estimated the OR, respective confidence intervals (95% CI), and probability values. Subgroup and interaction examinations were analyzed using multiple logistic regression, which included variables with at least a 0.20 probability of influencing the outcome. Missing data were excluded when they represented more than 40% of non-responses for the variable. The significance level was 5%. The program used was Stata (Stata Corp, LC), version 11.0.

Ethical and Legal Aspects of the Research

The research followed the criteria established in resolution 466/12 of the National Health Council, which regulates human beings’ studies. All participants signed the Informed Consent Form due to the inherent risks of losing medical records. These risks were minimal, and all records were consulted in the room where the hospital maintained the medical records. The research began after approval by the Research Ethics Committee of the ABC Medical School (Nº: 3.746,941).

Participants

During the period, 142 records were obtained, 3 of them excluded for not meeting the eligibility criteria. Hence, 139 medical records of patients with ICVA were included in the study.

Descriptive data

The profile of patients included in the study was: male (n=78; 56.12%), elderly (n=93; 66.91%) and history of current or previous smoking (n=79; 56.83%). Twenty-seven patients had diabetes (19.42%) and ninety-eight arterial hypertension (70.50%) (table 1).

During admission, 16.55% of patients had high blood pressure (n=23), 17.27% showed blood glucose level above 200mg/dl (n=24), 48.20% underwent cranial computed tomography (n=67). More than half of the patients (66.19%, n=92) did not have a high level of severity of injuries caused by ICVA, assessed by the NIHSS score above 15, with 52.52% having a stroke-to-thrombosis time greater than three hours (n=73) and 25.18% (n=35) had post-thrombolysis hemorrhagic transformation (table 2).

Outcome data

Of all patients, 18.71% of patients had no reduction in NIHSS score (n=26) (table 3).

Main results

The presence of diabetes was associated with a greater chance of not having a reduction in the NIHSS in the population studied, as patients with diabetes were 2.52 more likely to have no reduction in the NIHSS than patients without diabetes (OR = 3.52; 95% CI 1.37 to 9.06; p=0.009). The other sociodemographic characteristics were not associated with the non-reduction of the NIHSS (p>0.05) (table 3).

Of the clinical characteristics, only the presence of post-thrombolysis hemorrhagic transformation (p=0.002) was shown to be a risk factor, representing a 4.13-fold chance (CI 95% 1.68 to 10.16) of not reducing the NIHSS when compared to patients who did not present post-thrombolysis hemorrhagic transformation (table 4).

The multivariate analysis included sociodemographic or clinical characteristics that showed a trend towards non-reduction of the NIHSS (p<0.20). The examination also contained essential aspects such as gender, elderly, diabetes, and post-thrombolysis hemorrhagic transformation (table 5). We observed that the NIHSS non-reduction in the studied patients was influenced both by the existence of diabetes and the presence of post-thrombolysis hemorrhagic transformation, being respectively 192% and 317% more likely to have no reduction in the NIHSS (OR=2.92; 95% CI 1.05 to 8.17; p=0.040) and OR=4.17; 95% CI 1.59 to 10.98; p=0.004).

Main results

Approximately 18.5% of participants showed no clinical improvement (reduction in NIHSS score) after intravenous thrombolytic therapy. In these patients, the presence of diabetes and post-thrombolysis hemorrhagic transformation increased the risk of no clinical improvement by 192% (ranging from 5 to 717%) and 317% (ranging from 58 to 998%), respectively.

Limitations

It is a retrospective study in which the data sources were the patients’ hospital records can be recognized as a bias, given that the information was not collected for research. But it helps better understand health determinants, commonly used in scientific research worldwide³.

Another interesting fact that should be taken with caution is the interval estimates of the main results found in this study. It may have occurred because the sample selected for the study was small⁹, which may be due to incomplete data and the recruitment period of patients for inclusion in the study.

Its retrospective character and performance in a single specialized center are also limitations of this investigation. Another evident restriction is that this investigation does not have data on the long-term follow-up of the studied patients, which may be related to the precision bias of the estimates about patients with delayed recoveries.

On the other hand, the results of this research can favor greater effectiveness in implementing the thrombolysis protocol for patients diagnosed with ICVA. It also supports public policies to install an earlier treatment in the health care network, help identify patients who may not fully benefit from chemical thrombolysis alone and select those who may need adjunct therapy. Furthermore, this investigation can help the health professional predict early results, serving as a generator of hypotheses for future studies on chemical thrombolysis.

Interpretation

Many studies¹⁰ assess the determinants of early neurological degeneration, as it is crucial for the prognosis of patients affected by ICVA. It is one of the first studies to evaluate the determinants of no clinical improvement in patients after ICVA, regardless of early neurological degeneration.

This study sought to identify and describe some risk factors for clinical non-improvement based on the NIHSS score in ICVA victims undergoing intravenous thrombolysis with rt-PA. Although the risk factors found were diabetes and hemorrhagic transformation, there seems to be no relationship between them³.

Intracerebral hemorrhage is a significant complication related to the use of rt-PA, given its lethality, which affects approximately half of the patients in these conditions³, being a determinant for the non-improvement of the patients studied in the present study. However, the frequency (24.81%) of hemorrhagic transformation (symptomatic and asymptomatic) was lower than the findings by Ferreira et al. They reported 32.37% of hemorrhagic transformation frequency, 21% asymptomatic, and 10.98% symptomatic¹⁵.

Diabetes is a leading risk factor related to the non-clinical improvement of post-thrombolysis patients with rt-PA. It is already well known as a determinant of early post-ICVA neurological deterioration, mainly due to its relationship with hyperfibrinogenemia that directly impacts the cascade of coagulation¹⁴.

Despite being clinically relevant for a better patient prognosis, other factors were not associated with the lack of clinical improvement in patients with ICVA. This study found a trend towards males and being elderly as determinants of no clinical improvement according to the NIHSS score.

Most patients were male, similarly to other studies^16,17. In a cohort study, Savitz et al., showed that occlusive vascular lesions were more likely to recanalize in women than in men in response to intravenous thrombolytics¹⁸.

In the study, where the age equal to or over than 60 years showed a tendency to increase the risk of no clinical improvement, the mean age of participants was 66.14 years, close to that found in the literature^19,20. Engelter et al. showed that patients with CVA treated with intravenous rt-PA aged 80 years or more had a less favorable outcome than younger ones²¹. However, it is noteworthy that some studies show that the benefits of thrombolysis proved to be independent of age^20,21.

Age should not be an exclusion criterion to assess the possibility of using rt-PA, especially in those with good general health and no organ dysfunction. The increasing use of rt-PA in individuals over 80 years of age and its inclusion in clinical trials and randomized studies allowed conclusions about the benefits of these therapeutic strategies in this age group²¹. The possibility of elderly patients benefiting from thrombolysis is clinically relevant since age is one of the main determinants of disability and death in CVA patients²².

Other clinically vital factors such as a history of arterial hypertension, smoking, and clinical characteristics during admission did not show a statistical relationship with no clinical improvement²⁴.

The sample showed a high frequency of risk factors among the patients studied. Systemic arterial hypertension was the most prevalent comorbidity in the studied sample, as found in other studies^23,24. Data from the National Institute of Neurological Disorders and Stroke study and recent Canadian open-label research reported that blood glucose and uncontrolled blood pressure levels are markers of adverse outcomes in patients treated with thrombolysis²⁵. These outcomes corroborate our findings, in which most of the participants were hypertensive, and diabetes was a risk factor for no clinical improvement.

Simple measures to expedite thrombolytic therapy are crucial to reduce functional disability and mortality. In addition, it is essential to work on the prevention of modifiable risk factors to reduce the occurrence of CVA, emphasizing reducing the epidemiological rates of diabetes and health promotion measures focused on glycemic control.