J Thromb Thrombolysis (2014) 38:522–527 DOI 10.1007/s11239-014-1110-5

Acute ischemic stroke patients with diabetes should not be excluded from intravenous thrombolysis Blanca Fuentes • Andre´s Cruz-Herranz • Patricia Martı´nez-Sa´nchez • Ana Rodrı´guez-Sanz • Gerardo Ruiz Ares • Daniel Prefasi • Borja E. Sanz-Cuesta Manuel Lara-Lara • Exuperio Dı´ez-Tejedor



Published online: 8 July 2014 Ó Springer Science+Business Media New York 2014

Abstract The benefit of intravenous thrombolysis (IVT) has been questioned for patients with diabetes mellitus (DM) in cases of acute ischemic stroke (IS). Our objective was to analyze the differences in outcome according to prior diagnosis of DM and the use or not of IVT. Observational study with inclusion of consecutive IS patients admitted to an stroke unit. Demographic data, vascular risk factors, comorbidity, stroke severity and 3-month followup outcome (modified Rankin Scale) were compared according to prior diagnosis of DM and the use or not of IVT. A total of 1,139 IS patients were admitted; 283 (24.8 %) patients had a diagnosis of DM, and 261 were IVT treated (23.2 % of the group without DM and 21.9 % of the DM group). The IVT-treated patients with DM were older, had more comorbidities and had higher glucose levels on admission than those without DM and than IVTtreated patients. No significant differences in stroke severity, hemorrhagic transformation, in-hospital mortality or outcome at 3 months were found. The logistic regression analysis showed that stroke severity was associated with a higher risk of a poor outcome in IVT-treated patients, with no significant effect from DM after adjustment for confounders. Moreover, IVT was independently associated with a lower risk of poor outcome in DM patients (OR 0.49; 95 % CI 0.31–0.76; P = .002). DM patients should not be excluded from IVT, because DM is not associated

B. Fuentes (&)  A. Cruz-Herranz  P. Martı´nez-Sa´nchez  A. Rodrı´guez-Sanz  G. Ruiz Ares  D. Prefasi  B. E. Sanz-Cuesta  M. Lara-Lara  E. Dı´ez-Tejedor Department of Neurology and Stroke Center, IdiPAZ Health Research Institute, La Paz University Hospital, Autonomous University of Madrid, Paseo de la Castellana 261, 28046 Madrid, Spain e-mail: [email protected]

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with a poor outcome after IVT and this treatment is clearly beneficial for DM patients as compared with DM patients not treated with IVT. Keywords Stroke  Ischemic stroke  Diabetes  Intravenous thrombolysis  Outcome

Introduction Stroke in patients with diabetes mellitus (DM) has been associated with poorer outcomes compared with patients without DM, although there is still controversy regarding this point [1–7]. The reasons for the poorer prognosis in acute stroke patients with DM are not well known. Some possible contributing factors are poorer prestroke metabolic control [8], a higher risk of developing poststroke hyperglycemia [9] and the higher burden of other vascular risk factors and comorbidities [7]. Intravenous thrombolysis (IVT) is currently the standard treatment for acute ischemic stroke (IS). Patients with a prior diagnosis of DM are not restricted from treatment with IVT, and several studies have shown the safety and beneficial effects of IVT in patients with DM and prior stroke [10–12]. However, a lower frequency of IVT administration has been reported, which may reflect physician concerns about the risk of poor outcomes related to DM [13]. Some studies have suggested a poorer response to IVT in patients with metabolic syndrome [14] or with insulin resistance [15], and it has been reported that poststroke hyperglycemia may counterbalance the beneficial effect of IVT-induced recanalization [16, 17]; however, there is evidence that patients with DM obtain benefits from this therapy. A limitation in some studies addressing outcomes after IVT in patients with DM is the lack of a

Acute ischemic stroke patients

control group of patients with DM who were not treated with IVT. We hypothesize that IVT is safe and efficacious in IS patients with DM as compared with IVT-treated patients without DM and compared with non-IVT-treated patients with DM, when adjusted for stroke severity and glucose levels on admission, which are the primary prognostic factors in patients with IS. Thus, our aim was to analyze the differences in outcomes at 3 months according to prior diagnosis of DM and the use or not of IVT, taking into account the following: the prognostic influence of DM on outcome after IVT, and the effect of IVT on patients with DM as compared with patients with DM who are not treated with IVT.

Materials and methods We carried out an observational analysis of a stroke registry with prospective inclusion of consecutive patients with acute IS admitted to a stroke center at a university hospital from January 2006 to December 2010. The data from the patients with stroke were prospectively collected from medical records and were included in the stroke data bank, as has been previously described [18]. We analyzed the following variables: (a) baseline characteristics: age, sex and prestroke functional status by the modified Rankin Scale (mRS); (b) vascular risk factors and comorbid conditions: arterial hypertension, current smoking, diabetes mellitus (previous diagnosis and/or current treatment with insulin or oral hypoglycemic medications), hyperlipidemia, coronary artery disease, nonischemic cardiopathy, peripheral arterial disease, chronic or paroxysmal atrial fibrillation; (c) prestroke treatments; and (d) the Charlson-Deyo index (CDI) to quantify patients’ comorbidities. This index is a summary score based on the presence or absence of 17 medical conditions. A score of zero indicates that no comorbidities are present and higher scores indicate a greater burden of comorbidity. Consistent with previous studies, the scores of this index were dichotomized into low comorbidity (CDI \ 2) and high comorbidity (CDI C 2) [19]; (e) stroke severity on admission was evaluated using the National Institutes of Health Stroke Scale (NIHSS); (f) etiological stroke subtype, classified using published criteria such as atherothrombotic infarction, cardioembolic infarction, lacunar infarction, infarction of unusual cause and infarction of undetermined origin [20, 21]; (g) inhospital medical complications; and (h) outcome data: mortality and functional outcome at discharge assessed by the mRS score. Poor outcome was defined as an mRS [ 3. Patients who fulfilled the Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria for IVT [22] received IV tPA in a standard 0.9 mg/kg dose within

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3 h of stroke onset. Since the publication of the European Cooperative Acute Stroke Study III and data from the SITS registry, patients have been treated within a 4.5 h time window [23]. All the IVT-treated patients provided informed consent prior to IVT, which specifically included consent to include clinical data in a database that was approved by the La Paz University Hospital Ethics Committee for Clinical Research. A post-treatment CT scan was performed after 24 h or in case of neurological deterioration. Any grade of hemorrhagic transformation (symptomatic or not) was recorded in the database. The statistical analyses were performed with the SPSS package version 20 (Chicago, IL, USA) for Windows. The variables tested in the univariate analysis were baseline characteristics such as age, gender, medical history, prestroke treatments and ischemic stroke etiological subtype; and admission variables such as plasma glucose, blood pressure, stroke severity and HbA1c. The proportions between groups were compared with the Chi squared test. The continuous variables were tested using the t test or the Mann–Whitney test if normality was difficult to assume. P values\0.05 were considered significant. The prognostic effect of IVT and of prior diagnosis of DM were analyzed by multivariate logistic regression models. A backward procedure was followed as the modeling strategy, using the log likelihood ratio test to assess the suitability of fit and to compare nested models. Those variables that produced a change of C10 % of the odds ratio (OR) when eliminated were considered confounding variables. Variables with a value of P B 0.2 on univariate testing were included. Ninety-five percent confidence intervals (CIs) are presented.

Results A total of 1,139 acute IS patients were admitted; 283 (24.8 %) patients had previously known DM and 261 were treated with IVT (23.2 % no DM; 21.9 % DM). The baseline and demographic characteristics according to IVT treatment and the prior diagnosis of DM are shown in Table 1. IVT patients: DM vs. no DM The IVT-treated patients with DM had a higher frequency of hypertension and prior myocardial infarction, had used prestroke diuretics and statins more often, and had higher comorbidity, higher glucose levels and higher systolic blood pressure on admission than the IVT-treated patients without DM. There were no significant differences in stroke severity (Table 1). On admission, the HbA1c levels were measured in 127 (63.8 %) patients without DM and in 43 (69.4 %) patients with DM. The median HbA1c was higher in the patients with DM than in the patients without DM.

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Table 1 Baseline characteristics. Comparison of IS patients according to IVT treatment and with or without a diagnosis of DM IVT-treated Non-DM N = 199

Patients with DM DM N = 62

P

Non IVT N = 62 69.8 (11)

P

Age, mean (SD), years

66.9 (13)

ns

77.3 (9.6)

Men, n (%)

112 (56.3)

37 (59.7)

ns

142 (64.3)

37 (59.7)

ns

Medical history, n (%) Hypertension

111 (55.8)

53 (85.5)

.000

188 (85.1)

53 (85.5)

ns

77 (38.7)

27 (43.5)

ns

128 (57.9)

27 (43.5)

ns

Dyslipidemia

69.8 (11)

IVT N = 221

ns

Atrial fibrillation

33 (16.7)

10 (16.1)

ns

43 (19.5)

10 (16.1)

ns

Prior myocardial infarction

13 (6.5)

10 (16.1)

.036

22 (10)

10 (16.1)

ns ns

Arterial peripheral disease

2 (3.2)

ns

21 (9.5)

2 (3.2)

Cigarette smoking

47 (24.6)

4 (2)

18 (30.5)

ns

42 (19.1)

18 (30.5)

ns

Prior cerebral infarction

17 (8.5)

7 (11.3)

ns

49 (22.3)

7 (11.3)

ns

Charlson index C 2

18 (9.1)

26 (42.6)

.000

71 (43)

26 (42.6)

ns

61 (31)

24 (38.7)

ns

84 (38)

24 (38.7)

1 (1.6)

ns

35 (15.8)

Pre-stroke treatments, n (%) Antiplatelet drugs Oral Anticoagulants

5 (2.6)

1 (1.6)

ns .002

Statins

47 (23.9)

24 (38.7)

.033

91 (41.2)

24 (38.7)

.033

ACEI

37 (19)

15 (24.2)

ns

61 (27.6)

15 (24.2)

ns

Diuretics

35 (17.9)

20 (32.3)

.021

46 (20.9)

20 (32.3)

ns

ARB Beta-blockers

25 (12.8) 37 (19)

12 (19.4) 17 (27.4)

ns ns

50 (22.6) 31 (14.1)

12 (19.4) 17 (27.4)

ns .021

Calcium channel blockers

19 (9.7)

10 (16.1)

ns

40 (18.1)

10 (16.1)

ns

Oral antidiabetic drugs



43 (69.4)



140 (66.4)

43 (69.4)

ns

Insulin



11 (18.6)



61 (33.3)

11 (18.6)

.034

Ischemic Stroke etiological subtype Atherothrombotic

50 (25.1)

17 (27.4)

ns

63 (28.5)

17 (27.4)

ns

67(33.7)

24 (38.7)

ns

53 (24)

24 (38.7)

.025

Lacunar

22 (11.1)

6 (9.7)

ns

81 (36.7)

6 (9.7)

.000

Other or uncommon cause

10 (5)

1 (1.6)

ns

4 (1.8)

1 (1.6)

ns

Unknown

54 (27.1)

13 (21)

ns

27 (12.2)

13 (21)

ns

Cardioembolic

Admission variables Plasma glucose on admission (mg/dl), mean (SD)

115.7 (26)

160.8 (56)

.000

160.8 (60)

175.8 (78)

ns

Systolic blood pressure on admission (mmHg), mean (SD)

147.5 (31)

159.3 (25)

.029

153.7 (24)

159.3 (25)

ns

Diastolic blood pressure on admission (mmHg), mean (SD)

82.7 (16)

82.4 (16)

81.7 (15)

82.4 (16)

ns

Stroke severity-median NIHSS (IQR)

8 (11)

8 (13)

HbA1c %-median (IQR)

5.6 (4.7)

7.1 (7)

HbA1c mmol/mol-median (IQR)

37 (27.9)

54 (53)

No significant differences were found in the development of any grade of hemorrhagic transformation (12.9 % in the DM group vs. 8.2 % in the no DM group; P = .310). A total of 20 IVT-treated patients with IS died during hospitalization. There was a non-significant trend toward higher in-hospital mortality in the patients with DM than in the patients without DM (12.9 vs. 6.1 %; P = .101). Data regarding mRS at 3 months were available for 225 patients

123

ns ns .000

3 (7)

8 (13)

7.3 (9.3)

7.1 (7)

56 (78)

54 (53)

.000 ns

(86.2 %). Fifty-seven (33.9 %) IVT-treated IS patients without DM and 22 (38.6 %) patients with DM had poor outcomes at 3 months, without significant differences (P = .524). A shift analysis of the mRS scores at 3 months is represented in Fig. 1a. The results of logistic regression analysis to evaluate the influence of prior diagnosis of DM on outcome at 3 months for IVT-treated patients are shown in Table 2, adjusted for

Acute ischemic stroke patients

525

Fig. 1 Outcome at 3 months according to scores on the modified Rankin Scale: a IVTtreated patients. Comparison between patients with and without DM, P [ .05; b Patients with DM. Comparison between IVT and non IVT-treated patients, P [ .05

Table 2 Backward logistic analysis

Table 3 Backward logistic analysis

Unadjusted analysis

Adjusted analysis

OR

95 % CI

OR

95 % CI

Hypertension

1.52

0.82–2.79

.177

1.85

0.99–1.01

DM

1.31

0.66–2.58

.435

0.76

0.32–1.79

Prior myocardial infarction

3.81

1.22–11.8

.021







Charlson index C 2

1.00

0.43–2.36







HbA1c

1.36

1.00–1.86

.050







Glucose levels on admission

1.00

1.00–1.01

.024

1.85

0.89–3.83

NIHSS on admission

1.18

1.12–1.25

.000

1.19

1.12

P

1.00

Unadjusted analysis

Adjusted analysis

OR

95 % CI

P

OR

95 % CI

P

Pre-stroke insulin treatment

0.97

0.53–1.76

.934

1.13

0.57–2.22

.721

Pre-stroke anticoagulants

2.18

1.31–3.63

.003







Pre-stroke statins Pre-stroke betablockers

1.57 1.42

1.15–2.15 0.96–2.09

.004 .075

2.02 –

1.37–2.97 –

.000 –

.272

NIHSS on admission

1.20

1.16–1.24

.000

1.24

1.19–1.28

.000

.000

Intravenous thrombolysis Cardioembolic stroke

1.36

0.98–1.88

.060

0.49

0.31–0.76

.002

3.05

2.22–4.20

.000







P .095 .535

Poor outcome at 3 months in IVT-treated patients

baseline differences between patients with and without DM. The following variables were included in the maximum model: DM, hypertension, prior myocardial infarction, HbA1c, Charlson Index C 2, glucose levels on admission and stroke severity on admission. The backward multivariate analysis showed that NIHSS on admission was the only factor independently associated with a higher risk of a poor outcome at 3 months (OR 1.19; 95 % CI 1.12–1.25; P = .000), with no significant effect from DM after adjustment for confounders. Patients with DM: IVT treated vs. no IVT The patients with DM who did not receive IVT had less severe strokes, had a higher percentage of lacunar strokes, were more frequently on treatment with insulin, oral

Poor outcome at 3 months in patients with DM

anticoagulants and statins, and had a lower frequency of prior treatment with beta-blockers than IVT-treated patients with DM. There were no significant differences in vascular risk factors, comorbidity, Hb1Ac levels, glucose levels or systolic blood pressure on admission (Table 1). Hemorrhagic transformation was more frequent in the IVTtreated group (12.9 vs. 4.5 %; P = .033). A total of 62 patients with DM died during hospitalization. There was a non-significant trend toward higher in-hospital mortality in IVT-treated patients than in patients not treated with IVT (12.9 vs. 7.2 %; P = .195). Data regarding mRS at 3 months were available for 206 patients (72.8 %). Fiftyfive (36.9 %) of the non-IVT-treated IS patients and 22 (38.6 %) patients treated with IVT had poor outcomes at

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3 months, without significant differences (P = .873). A shift analysis of the mRS scores at 3 months is represented in Fig. 1b. The results of logistic regression analysis to evaluate the influence of IVT on outcome at 3 months in patients with a history of DM are shown in Table 3, adjusted for baseline differences between patients treated with IVT or not. The following variables were included in the maximum model: pre-stroke treatment with anticoagulants, insulin, statins, beta-blockers, IVT treatment, cardioembolic stroke and stroke severity on admission. The backward multivariate analysis showed that IVT was independently associated with a lower risk of a poor outcome at 3 months (OR 0.49; 95 % CI 0.31–0.76; P = .002).

Discussion Our study shows that in clinical practice patients with DM obtain similar benefits from IVT thrombolysis as patients without DM, despite being older and having higher comorbidity. The primary factor associated with a poorer response to IVT is stroke severity, with no significant influence from DM diagnosis. Although DM itself is not considered an exclusion criteria for IVT, a significantly lower frequency of IVT administration in patients with DM has been reported [13]. The National Institute of Neurological Disorders and Stroke trials that demonstrated the efficacy of IVT did not exclude patients with DM [24]. A post hoc analysis to identify subgroups of stroke patients for whom thrombolytic therapy was particularly hazardous concluded that no evidence was found to justify withholding IVT from any of the subgroups studied (including DM) [25]. In addition, the analysis of large stroke registries such as the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITSISTR) and the Virtual International Stroke Trials Archive (VISTA) concluded that outcomes from thrombolysis are better than those of controls for patients with DM [11]. Thus, why the lower frequency of IVT use in IS patients with DM? Lower IVT use does not appear to be related to contraindications for IVT, because a comparison of the frequencies of documented contraindications and warnings about rt-PA treatment between patients with and without DM found them to be almost identical. However, physician concerns regarding the risk of poor outcomes related to DM could contribute to the lower frequency of use [13]. Along these lines, one of the more dangerous complications is the possibility of hemorrhagic transformation of a cerebral infarction. However, this complication was not found to be related to DM in our study, which is in agreement with other published studies [26, 27]. In addition, DM was not associated with a risk of developing

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cerebral edema after IVT [28], and DM was not found to be linked with early neurological deterioration after IVT [29, 30]. Finally, with regard to the resistance to arterial recanalization, few studies have systematically examined the rates of arterial recanalization in patients with DM versus patients without DM [31]. Some of the studies that have explored the predictors for poor recanalization found post-stroke hyperglycemia, not DM, to be independently associated with poor recanalization after IVT [17, 32]. Studies that have reported poorer responses to IVT in diabetic patients have lacked an adequate control group of patients with DM who had not been treated with IVT [33]. Randomization in blocks based on diabetic status in future acute stroke thrombolysis trials has been suggested [33]. However, a positive beneficial effect from this therapy could not be ruled out, even if it was of less benefit than in patients without DM. Although tempting, from a statistical point of view it is wrong to select a subgroup in which the proportion of favorable outcomes was lower and conclude that IVT is not beneficial for that subgroup [25]. In addition, various observational studies that addressed factors associated with poor stroke outcome and in-hospital mortality in IS patients with DM did not include information regarding the administration of IVT [7, 34]. We also analyzed outcomes in patients with DM according to the administration of IVT and found that IVT was associated with a significantly lower risk of poor outcomes at 3 months after adjusting for confounding factors. As mentioned earlier, an analysis of large registries such as the SITS-ISTR and the VISTA concluded that outcomes from thrombolysis are better than those of controls in patients with DM [11]. Our study has several limitations. The first is based on using a unicenter registry, in which a selection bias cannot be excluded. Second, we did not register arterial recanalization after IVT, nor infarct volume. Finally, approximately 14 % of the IVT-treated patients were lost from follow up at 3 months. However, two strengths of our study are the fact that the rate of IVT was similar between patients with and without DM and that the rate was quite high (more than 20 % of patients with acute IS admitted to the stroke unit), revealing strong adherence to current management of acute IS guidelines. Another strength is the analysis of patients not treated with IVT. In conclusion, DM itself is not associated with poor outcome after IVT, and IVT treatment is clearly beneficial for DM patients compared with patients not treated with IVT. There is no evidence-based rationale for excluding patients with DM from IVT and this therapy has shown better outcomes in patients with IS, including those with DM. Thus, more effort should be made to ensure the best management of acute IS patients with DM, which includes IVT in those cases with no contraindications.

Acute ischemic stroke patients Acknowledgments We thank Juliette Siegfried and her team at ServingMED.com for editorial assistance. The Department of Neurology at La Paz University Hospital belongs to the INVICTUS Stroke Research Network (Instituto de Salud Carlos III, Ministerio de Economı´a y competitividad (RD12/0014/0006).

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17.

18. Conflict of interest The authors declare that they have no conflicts of interest. 19.

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Acute ischemic stroke patients with diabetes should not be excluded from intravenous thrombolysis.

The benefit of intravenous thrombolysis (IVT) has been questioned for patients with diabetes mellitus (DM) in cases of acute ischemic stroke (IS). Our...
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