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The association between t-PA administration and in-hospital mortality following acute ischemic stroke in Puerto Rican patients.

Acute ischemic stroke (AIS) remains a significant cause of mortality and morbidity worldwide (1). In the United States, approximately 130,000 individuals die each year from acute strokes (2), and approximately one third of acute stroke patients develop disabilities as a result of their strokes (3).

Several randomized controlled studies have evaluated the effectiveness of early intravenous tissue plasminogen activator (t-PA) treatment at improving stroke symptoms while also reducing both disability and mortality. The results of several AIS follow-up meta-analyses have also suggested that intravenous t-PA therapy improves survival and quality of life (4-8).

Since receiving the Food and Drug Administration's (FDA) approval in 1996, thrombolytic therapy with t-PA has become accepted as the most effective intervention in terms of limiting ischemic tissue damage in AIS patients (9) and is considered the standard of care for AIS. Yet, despite these advances, the proportion of AIS patients treated with t-PA is still low, while stroke mortality remains high (1, 5). Possible explanations for those findings include the narrow time window (within 4.5 hours of symptom onset) in which thrombolytic therapy must be initiated and the higher risks of both symptomatic intracerebral hemorrhage (ICH) and short-term death associated with thrombolytic therapy administration (9-12). Finally, there is conflicting evidence regarding t-PA's benefit in terms of its reducing overall mortality in different populations (13-15).

The prevalence of stroke in Puerto Rico (1.9%) is slightly lower than the overall prevalence of stroke in the United States (2.6%) (1). However, very few studies have reported on the rate of t-PA administration and its impact on in-hospital mortality (IHM) in patients hospitalized in Puerto Rico (16). For that reason, we aimed to determine the following in AIS patients hospitalized in Puerto Rico: 1) the rate of t-PA treatment; 2) the effect of t-PA treatment on IHM; and 3) the explanatory variables for the association between t-PA administration and IHM risk.

Methods

Study design

We performed a secondary analysis of the data from patients of the Puerto Rico Cardiovascular Disease Surveillance System (PRCDSS), which has a non-concurrent prospective study design.

Population and Database description

Puerto Ricans are mostly Hispanics. The PRCDSS collected information about adult (18 years old and older) patients living in Puerto Rico, who had been hospitalized with acute myocardial infarction, heart failure, or stroke. This study included only PRCDSS patients with AIS. The data collection for the PRCDSS followed an adapted standardization of methods developed for the Worcester Heart Attack Study (17). An electronic database was established to collect data from the medical records of patients with ICD-9 codes 434 (occlusion of cerebral artery) and 436 (acute but ill-defined cerebrovascular disease), as reported by a total of 21 medical centers with acute care facilities in the years of 2007, 2009, and 2011. Only the records of patients with an AIS diagnosis validated by CT or MRI and of patients admitted with an initial acute stroke during the 3 study years were included. Patients with transient cerebral ischemia (ICD-9 code 435.9) were excluded.

The collected patient information included demographics, medical history, and clinical symptomatology on presentation as well as physical exam findings, mode of transportation to the hospital, treatment administered, and IHM.

Variables

The independent variable was the administration of t-PA within 4.5 hours of symptom onset. The dependent variable was IHM as reported by the discharge status in the medical records. Patient information regarding comorbidities including obesity (defined as a BMI [greater than or equal to] 30 Kg/m2), dyslipidemia, diabetes, hypertension, atrial fibrillation, smoking status, hospital arrival mode, demographics (including gender and age), concomitant anticoagulant medications, and symptomatic ICH were also analyzed for their potential roles as confounders. The definitions of these variables are listed in Appendix A.

Data analysis

We performed a preliminary exploratory data analysis to identify outliers and patterns of missing data. Subsequently we evaluated the crude proportion of IHM in patients who had received t-PA. We then conducted a bivariate analyses to test the association of potential confounding variables with IHM. Statistical differences between categorical variables were tested using chi-square statistics. Lastly, we used multivariate logistic regression models to evaluate the independent association between t-PA administration and IHM. To test the desired level of independence and to select the correct variables (adequacy), we evaluated a parsimonious model including variables associated with both dependent and independent variables in our sample (Model 1) (18), as well as variables of clinical relevance reported in the published literature (Model 2). P-values less than 0.05 were considered for statistical significance for a 2-tailed test. Analyses were performed using IBM SPSS Statistics for Windows, Version 20 (IBM Corp., Armonk, NY: IBM Corp.) (19). The Institutional Review Boards of Florida International University and University of Puerto Rico Medical Sciences Campus approved this study.

Results

A total of 1968 patients were admitted to 21 hospitals in Puerto Rico in 2007, 2009, and 2011--each with a CT- or MRI-confirmed diagnosis of AIS--and were included in this study. Of these, 104 (5%) patients received t-PA treatment. Eighty-five patients died during their stay in the hospital: 80 (4%) of those in the non-t-PA group and 5 (5%) of those in the t-PA group (Table 1). Twelve (60%) hospitals were considered to be "academic," according to the Association of American Medical Colleges definition of "teaching status" (20).

Overall, 71% of the patients were younger than 79 years old, 52% were women, and 18% were obese. Hypertension was the most common comorbidity, affecting 95% of patients, followed by hyperlipidemia (62%) and diabetes mellitus (55%). About 9% of the sample patients were current smokers, 5% had reported excessive alcohol use, and 85% were currently taking anticoagulation medication. Women received significantly less t-PA than did their male counterparts (p = 0.004). Of all patients, those who received t-PA were significantly less likely to have hypertension (p = 0.016) than were those who did not (Table 1).

An additional analysis conducted with a similar number of patients (N = 110) not receiving t-PA and paired by gender, age, and selected comorbidities (along with having had t-PA administered within 4.5 hours of the onset of symptoms) showed results similar to those of the original analysis with 1864 patients indicated in Table 1 (data not shown).

Table 2 shows the results of the multivariate analysis. In Model 1, we only adjusted for patient gender and history of excessive alcohol use. In addition to patient gender and history of excessive alcohol use, in Model 2 we further adjusted for BMI, history of hypertension, presence of hyperlipidemia, presence of diabetes, concomitant use of anticoagulant medication, presence of atrial fibrillation, smoking status, mode of arrival at the hospital, radiologic imaging method used for diagnosis, and presence of intra-cranial hemorrhage. In these patients, the receipt of t-PA was not significantly associated with IHM (OR = 1.26, 95% CI = 0.49-3.23 and OR=2.49, 95% CI = 0.81-7.66 in Models 1 and 2, respectively) (Table 2). In the adjusted analysis, women no longer had increased odds for IHM (OR 1.76, 95% CI = 0.91-3.39) and patients with hyperlipidemia did not have decreased odds for IHM (OR 0.78, CI = 0.44-1.39). However, other variables were found to be independently associated with IHM; notably, patients receiving concomitant anticoagulation were 58% less likely to die (OR = 0.42, 95% CI = 0.20-0.88), while age (>80 years) (OR = 2.03, 95% CI = 1.13-3.68), obesity(OR = 1.88, 95% CI = 1.01-3.49), and mode of arrival (by ambulance as opposed to walking in or arriving in a car or other kind of vehicle) OR = 3.61, 95% CI = 1.95-6.68) increased the odds of IHM.

Discussion

We found no evidence for an association between the receipt of t-PA and IHM in patients of the PRCDSS.

Many randomized controlled trials have evaluated the ability of intravenous t-PA to reduce overall mortality in patients with AIS, albeit with varying results, as detailed in the meta-analysis by Wardlow et al. (5). Yet, few studies have analyzed the risk of IHM associated with intravenous t-PA use, and fewer still have done so in a predominantly Hispanic population. Our results of short-term mortality compare with those from the trial by the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (9), in which mortality throughout the 90 days of follow-up did not differ between groups treated with t-PA and those not so treated.

Several patient characteristics were found independently associated with IHM. Patients who received concomitant anticoagulation therapy demonstrated 58% lower odds of dying before being discharged, while patients of advanced age, who suffered from obesity, and whose mode of arrival at the hospital was an ambulance exhibited higher odds of dying before being discharged. A potential mechanism explaining the lower odds of IHM among patients receiving concomitant anticoagulants is that these patients might suffer less severe ischemic strokes compared to patients not receiving concomitant anticoagulants. Such a mechanism is supported by the scientific literature (21). For example, evidence supports the assertion that warfarin alone, even at sub-therapeutic dosages, decreases the initial stroke severity and the risk of re-occlusion after t-PA therapy (22, 23). In contrast, other studies have reported no association between any concomitant anticoagulation medication and IHM. An observational study which included 23,487 patients from the American Heart Association Get With The Guidelines-Stroke Registry, found that mortality in patients after intravenous t-PA treatment was not significantly different between the warfarin-treated and non-warfarin-treated groups (OR = 0.94, 95% CI = 0.79-1.13) (21). In a similar study of 1,739 patients in Canada, Vergouwen et al. reported that the preadmission use of warfarin was not associated with IHM (OR = 0.6, 95% CI = 0.3-1.0) (24). It must be noted that these studies included only patients treated with sub-therapeutic doses of warfarin (International Standardized Ratio<1.7), while our current analysis includes those patients treated with any dose of warfarin. Therefore, in our sample we might have higher rates of patients with therapeutic doses of anticoagulants, which could explain the presence of an association and the discrepancy between the two studies' results. Such factors merit future investigation.

Advanced age was also found to be associated with a twofold increased rate of IHM, which is consistent with previous reports. Kammersgaard, in a review of the Copenhagen Stroke Study, found age to be the most significant risk factor affecting short-and long-term post-stroke survival (25). Similarly, in a study analyzing the impact of the time of hospital admission on stroke outcomes involving 907 patients in Germany, older age (OR = 1.05 per year increase, 95% CI = 1.004-1.09) was associated with increased short-term mortality in t-PA-treated patients (26). Additionally, in a recent retrospective observational study of the Nationwide Inpatient Sample, a greater than twofold increase in IHM was reported in patients over 80 years old compared to their younger counterparts (27).

Regarding the independent association of obesity with IHM, most evidence suggests that increased body weight is associated with greater mortality in stroke patients (28-31). Our results were similar, showing that obesity was associated with an almost twofold increase in the odds of IHM.

In our study, patients who arrived at the hospital by ambulance were 3.7 times more likely to die before being discharged, which is contradictory to findings currently reported in the scientific literature (5, 32). There are few potential explanations for this fact: more severe AIS cases may arrive by ambulance; the emergency medical services (EMS) team might be responding in an untimely manner; or a potential lack in the geographical coverage of the local EMS provider may play a role. Unfortunately, the information available in the PRCDSS database is not sufficient for the testing of any of these hypotheses.

The PRCDSS is the first ongoing surveillance effort conducted in Puerto Rico whose aim is to systematically evaluate the therapeutic management and outcomes of patients hospitalized with AIS. Findings from this study contribute to the growing literature on t-PA treatment for AIS by providing evidence collected from a mostly Hispanic population. However, our finding that there is no association between t-PA treatment and IHM should be interpreted with caution: We had no data on either stroke severity or the interval between symptom onset and treatment time. Thus, we cannot rule out the possibility that these potential discrepancies between the different t-PA treatment groups were responsible for the lack of association (per our study) between t-PA treatment and IHM.

In conclusion, we found evidence that intravenous t-PA therapy was not associated with the risk of IHM in patients with AIS in Puerto Rico. While our findings suggest that t-PA is an intervention that may not lead to an increase in short-term mortality, further studies exploring the risks of disability and long-term mortality in the Puerto Rican AIS population are warranted to provide further evidence for the overall efficacy and safety of t-PA. Future studies might help provide further support to programs aimed at increasing the awareness of the efficacy and safety of t-PA among both medical providers and the public, ultimately improving the quality of health care for AIS patients.

Acknowledgments

We are sincerely grateful to Gretel Castro, MPH, and Pura Rodriguez de la Vega, MPH, from the Department of Medical and Health Sciences Research, Florida International University Herbert Wertheim College of Medicine, for the biostatistics support and assistance.

References

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(5.) Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke an updated systematic review and meta-analysis. Lancet 2012;379:2364-72.

(6.) Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017-25.

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(13.) Nasr DM, Brinjikji W, Cloft HJ, Rabinstein AA. Racial and ethnic disparities in the use of intravenous recombinant tissue plasminogen activator and outcomes for acute ischemic stroke. J Stroke Cerebrovasc Dis 2013;22:154-60.

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(17.) Goldberg RJ, Spencer FA, Yarzebski J, et al. A 25-year perspective into the changing landscape of patients hospitalized with acute myocardial infarction (the Worcester Heart Attack Study). Am J Cardiol 2004;94:1373-8.

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(19.) IBM Corp. IBM SPSS Statistics for Windows. Version 20.0. Armonk, NY: IBM Corp; 2011.

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Appendix A

Variable                Definition

t-PA administration     Defined as the receipt of any dose of t-PA
                          within 4.5 hours of onset of AIS symptoms
In-hospital mortality   Defined as death before discharge from
                          medical center; obesity defined as a
                          body mass index [greater than or equal
                          to] 30 kg/[m.sup.2]
Dyslipidemia            Individuals were identified as having
                          dyslipidemia if they mentioned before
                          admission and/or use of lipid-lowering
                          agents during hospitalization and/or
                          discharge
Diabetes                Individuals were identified as having
                          diabetes mellitus (regardless of
                          type) if mentioned before admission
                          and/or use of hypoglycemic/insulin before
                          admission, during hospitalization, and/or
                          discharge
Hypertension            Individuals were identified as hypertensive
                          if mentioned before admission and/or use
                          of antihypertensive drugs during
                          hospitalization and/or discharge
Atrial fibrillation     Individuals were identified as having atrial
                          fibrillation if mentioned before admission
                          and/or occurred during hospitalization
                          and/or at discharge
Smoking status          Defined as currently smoking or not
                          currently smoking
Hospital arrival        Defined by emergency medical service/
  mode                    ambulance or by taxi/private vehicle
Gender                  Defined as man or woman
Age                     Individuals were grouped into the following
                          age groups: [less than or equal to] 79
                          years old and [greater than or equal to]
                          80 years old
Concomitant anti        Individuals were identified as taking
  -coagulant              concomitant anti-coagulant medication
  medication              if warfarin was used during
                          hospitalization
Symptomatic             Defined as the diagnosis of ICD-9 code 432
  intracerebral           and verified by imaging
  hemorrhage
Alcoholism/Excessive    Individuals were identified as using
  alcohol use             excessive amounts of alcohol if any of
                          the following phrases were used in their
                          medical charts: excess alcohol use/heavy
                          drinking/alcohol use disorder/alcohol
                          abuse.


Kevin Shah, BS *; Samuel Kohrman, BS *; Suehyb Alkhatib, MS *; Juan Gonzalez, MD ([dagger]); Fernando Santiago, MD ([dagger]); Marcia Varella, MD, PhD *; Juan Zevallos, MD *

* Herbert Wertheim College of Medicine, Florida International University, Miami, Florida; ([dagger]) University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico

The authors have no conflicts of interest to disclose.

Address correspondence to: Kevin Shah, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, AHC 2, Miami, Florida 33199. Email: kshah011@fiu.edu
Table 1. Characteristics of stroke patients in the Puerto
Rico Cardio-vascular Disease Surveillance System who were
treated with t-PA

                                t-PA administered

Variable                        % Yes       % No
                                (N = 104)   (N = 1864)

In-hospital mortality (IHM)     4.80        4.30
Age [greater than or equal      29.80       29.10
  to]80 (1)
Gender (being a woman)          35.50       52.90
Obese BMI (kg/[m.sup.2]) (2)    18.40       24.30
Diabetes mellitus               54.10       55.50
Current smoker                  11.60       9.30
Alcoholism/excessive            2.30        6.5
  alcohol use *
EMS/ambulance (3)               46.90       44.10
ICH                             10.00       2.30
Atrial fibrillation             7.10        8.00
Hyperlipidemia                  65.90       61.90
Hypertension                    89.50       95.10 *
Anticoagulation                 78.80       85.50

Variable                        Total (N)   p-value

In-hospital mortality (IHM)     85          0.803
Age [greater than or equal      569         0.885
  to]80 (1)
Gender (being a woman)          1017        0.004
Obese BMI (kg/[m.sup.2]) (2)    357         0.246
Diabetes mellitus               937         0.801
Current smoker                  167         0.455
Alcoholism/excessive            102         0.116
  alcohol use *
EMS/ambulance (3)               821         0.586
ICH                             41          0.722
Atrial fibrillation             130         0.787
Hyperlipidemia                  1036        0.455
Hypertension                    1741        0.016
Anticoagulation                 1658        0.063

t-PA = tissue plasminogen activator; BMI = body mass index;
EMS = emergency medical services; ICH = intracerebral
hemorrhage; 1--Reference age group was <80 years of
age; 2--Non-obese includes overweight, normal weight,
and underweight patients (by BMI); 3--Reference was
using personal car or walking in. * Alcoholism/excessive
alcohol use: if "excess alcohol use/heavy drinking/
alcohol use disorder/alcohol abuse" was ever
mentioned in the medical history.

Table 2. Adjusted multivariate analysis identifying odds of in-hospital
mortality in the Puerto Rico Cardiovascular Disease Surveillance
System for all potential confounding variables for stroke outcomes

                                      In-hospital mortality (IHM)

                                    Model 1            Model 2

                                OR     95% CI      OR     95% CI

t-PA administered               1.26   0.49-3.23   2.49   0.81-7.66
Gender (being a woman)          1.65   1.03-2.64   1.76   0.91-3.39
Alcoholism/excessive
alcohol use *                   0.45   0.11-1.87   0.82   0.18-3.72
Age [greater than or                               2.03   1.13-3.68
  equal to]80 (1)
Obese BMI (Kg/[m.sup.2]) (2)                       1.88   1.01-3.49
Diabetes mellitus                                  1.05   0.60-1.85
Current smoker                                     0.76   0.22-2.67
MRI (3)                                            1.16   0.63-2.12
EMS/ambulance (4)                                  3.61   1.95-6.68
ICH                                                0.86   0.10-7.26
Atrial fibrillation                                1.44   0.60-3.48
Hyperlipidemia                                     0.78   0.44-1.39
Hypertension                                       3.28   0.42-25.61
Anticoagulation                                    0.41   0.20-0.88

t-PA = tissue plasminogen activator; BMI = body mass index;
EMS = emergency medical services; ICH = intracerebral hemorrhage.
1--Reference age group was <80 years of age; 2--Non-obese includes
overweight, normal weight, and underweight patients (by BMI);
3--Reference imaging modality was CT; 4--Reference was using
personal car or walking in. * Alcoholism/excessive alcohol use:
if "excess alcohol use/heavy drinking/alcohol use disorder/alcohol
abuse" was ever mentioned in the medical history.
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Author:Shah, Kevin; Kohrman, Samuel; Alkhatib, Suehyb; Gonzalez, Juan; Santiago, Fernando; Varella, Marcia;
Publication:Puerto Rico Health Sciences Journal
Article Type:Report
Date:Dec 1, 2016
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