Circadian variation in the effect of intravenous thrombolysis after non ...

J Thromb Thrombolysis (2014) 38:253–259 DOI 10.1007/s11239-013-1041-6

Circadian variation in the effect of intravenous thrombolysis after non-lacunar stroke Manuel Cappellari • Paolo Bovi • Giuseppe Moretto

Published online: 9 January 2014 Ó Springer Science+Business Media New York 2014

Abstract The onset of non-lacunar stroke symptoms has a circadian variation, with a higher risk in the early morning hours and lower risk during the nighttime period, but this circadian distribution has not been clearly established on the effect of intravenous (IV) thrombolysis. The aim of the present study was to assess whether the time interval based on time of Alteplase IV infusion may influence the effect of treatment in patients with non-lacunar stroke. We conducted an analysis on prospectively collected data of 476 non-lacunar stroke patients treated with IV thrombolysis. To identify a possible circadian variation in the effect of Alteplase IV infusion, we used the following outcome measures: major neurological improvement (NIH stroke scale [NIHSS] score decrease of B8 points from baseline or NIHSS score of 0 at 24 h), and hemorrhagic transformation according to European Cooperative Acute Stroke Study trial definition within 24 h. Multivariate analysis showed that ORs for major neurological improvement were lower in patients who started IV thrombolysis in the 6 AM–noon interval (OR 0.35, 95 % CI 0.16–0.74, p = 0.006) and noon–6 PM interval (OR 0.40, 95 % CI 0.20–0.81, p = 0.010), whereas ORs for hemorrhagic transformation were lower in patients who started IV thrombolysis in the noon–6 PM interval (OR 0.29, 95 % CI 0.12–0.67, p = 0.004) and in the 6 PM–midnight interval (OR 0.26,

95 % CI 0.11–0.62, p = 0.002), compared with midnight– 6 AM interval. The effect of Alteplase IV infusion could show a circadian variation in patients with non-lacunar stroke. After comparison with the midnight–6 AM interval, thrombolysis could be more safe from noon to midnight, and less effective from 6 AM to 6 PM. Keywords Circadian Stroke Outcome Thrombolysis Fibrinolysis Alteplase

Introduction Strong evidences have reported that the onset of ischemic stroke symptoms has a circadian variation, with a higher risk in the early morning hours (6 AM to noon) and lower risk during the nighttime period (midnight to 6 AM) [1], but this circadian distribution has not been reported in patients with lacunar stroke [2]. So far, a circadian variation of the effect of intravenous (IV) thrombolysis has not been clearly established. We assess whether the time interval based on time of IV thrombolysis may influence the effect of treatment in patients with non-lacunar stroke.

Methods Electronic supplementary material The online version of this article (doi:10.1007/s11239-013-1041-6) contains supplementary material, which is available to authorized users. M. Cappellari (&) P. Bovi G. Moretto Stroke Unit, Division of Neurology, Department of Neuroscience, Azienda Ospedaliera Univarsitaria Integrata Verona, Piazzale A. Stefani 1, 37126 Verona, Italy e-mail: [email protected]

We conducted a retrospective analysis based on data prospectively collected from 476 consecutive patients with diagnosis of non-lacunar stroke at discharge, according to trial of ORG 10172 in acute stroke treatment (TOAST) criteria [3], who were admitted to the Stroke Unit of the Division of Neurology, Verona General Hospital, from December 2004 to February 2013. After informed consent,

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the patients underwent IV thrombolysis according to current European Alteplase license, or beyond the license. For comparison with previously published studies of circadian distribution and time of stroke onset [1, 2], we used the following 6-h time blocks based on time of Alteplase IV infusion: midnight–6 AM (00:00–05:59 h), 6 AM–noon (06:00–11:59 h), noon–6 PM (12:00–17:59 h), and 6 PM– midnight (18:00–23:59 h). To identify a possible circadian variation in the effect of thrombolysis, we used the following primary outcome measures: major neurological improvement (NIH Stroke Scale [NIHSS] score decrease of B8 points from baseline or NIHSS score of 0 at 24 h) and hemorrhagic transformation according to European Cooperative Acute Stroke Study (ECASS) trial definition (hemorrhagic infarction [HI1, HI2], parenchymal hemorrhage [PH1, PH2], and remote parenchymal hemorrhage [PHr1, PHr2] within 24 h) to estimate the efficacy and safety of Alteplase IV infusion, respectively [4, 5]. For comparison with previously published studies of circadian distribution and time of Alteplase IV infusion [6–8], we used the following secondary outcome measures: symptomatic intracranial hemorrhage (sICH) according to NINDS study definition (NIHSS score increase of C1 point from baseline or death with any intracranial hemorrhage within 7 h) [9], sICH according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition (NIHSS score increase of C4 points from baseline or death with local or remote parenchymal hematoma type 2 within 36 h) [10], sICH according to ECASS III definition (NIHSS score increase of C4 points from baseline or death with any intracranial hemorrhage within 7 days) [11], excellent (modified Rankin Scale [mRS] score B1) and favourable (mRS score B2) functional outcome at 3 months [12], and mortality at 3 months [12]. As the reference, we used patients who started Alteplase IV infusion from midnight to 6 AM according to previous studies that reported a lower risk of ischemic stroke in this time interval [1, 2]. We examined differences between the midnight–6 AM group and other three groups defined according to 6-h time intervals using the Chi square test (Fisher’s exact test) for categorical variables, and the t test and the Mann–Whitney U test for continuous and ordinal variables, respectively. We estimated the prognostic effect of 6 AM–noon, noon–6, and 6 PM–midnight intervals compared with midnight–6 AM interval, by calculating the odds ratio (OR) with two-sided 95 % confidence intervals (CI) for outcome measures, establishing statistical significance at two-tailed 0.05 level (p \ 0.05). We performed an adjusted analysis (logistic regression) of the outcome measures using a backward method that included established all

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variables with a probability value \0.10 in univariate analysis.

Results Of the 476 patients included in the study, 51 (10.7 %) were treated in the midnight–6 AM interval, 116 (24.4 %) in the 6 AM–noon interval, 161 (33.8 %) in the noon–6 PM interval, and 148 (31.1 %) in the 6 PM–midnight interval. Supplementary figure 1 and 2 show the distribution of number of patients based on time of stroke onset and Alteplase IV infusion during the 24 h, respectively. Table 1 shows the clinical characteristics of the cohort and the four time intervals groups of patients. No significant differences were observed between the midnight– 6 AM group and other three groups. Major neurological improvement at 24 h was noted in 148 (31.1 %) patients of the cohort and in 25 (49 %) patients thrombolysed in the midnight–6 AM interval. Multivariate analysis showed that ORs for major neurological improvement were lower in patients who started IV thrombolysis in the 6 AM–noon interval (OR 0.35, 95 % CI 0.16–0.74, p = 0.006) and noon–6 PM interval (OR 0.40, 95 % CI 0.20–0.81, p = 0.010), compared with midnight–6 AM interval. ORs for major neurological improvement were not different between patients who started IV thrombolysis in the 6 PM–midnight and midnight–6 AM intervals (Table 2). Hemorrhagic transformation within 24 h was noted in 82 (17.2 %) patients of the cohort and in 14 (27.5 %) patients thrombolysed in the midnight–6 AM interval. Multivariate analysis showed that ORs for hemorrhagic transformation were lower in patients who started IV thrombolysis in the noon–6 PM interval (OR 0.29, 95 % CI 0.12–0.67, p = 0.004) and in the 6 PM–midnight interval (OR 0.26, 95 % CI 0.11–0.62, p = 0.002), compared with midnight–6 AM interval. ORs for hemorrhagic transformation were not different between patients who started IV thrombolysis in the 6 AM–noon and midnight–6 AM intervals (Table 2). sICH by NINDS study definition was noted in 32 (6.7 %) patients of the cohort, sICH by SITS-MOST definition in 18 (3.8 %), sICH by ECASS III definition in 28 (5.9 %), excellent functional outcome in 212 (45.3 %), favourable functional outcome in 271 (57.9 %), and mortality in 57 (12.2 %). Of the patients thrombolysed in the midnight–6 AM interval, sICH by NINDS study definition was noted in 4 (7.8 %), sICH by SITS-MOST definition in 4 (7.8 %), sICH by ECASS III definition in 5 (9.8 %), excellent functional outcome in 29 (56.9 %), favorable functional outcome in 32 (62.7 %), and mortality in 7 (13.7 %). On multivariate analysis, ORs for secondary

66.5 ± 11.3

227 (47.7)

Dose of IV Alteplase

Off-label thrombolysis

41 (8.6)

25 (5.3)

Prior stroke [3 months

Congestive heart failure

146.5 ± 22.3

17 (3.8)

82 (18.6)

132.6 ± 45.6

150.8 ± 20.9

81.1 ± 11.9

CT sign of current infarct

MCA hyperdensity

Blood glucose (mg/dL)

SBP (mmHg)

DBP (mmHg)

99 (20.8)

199 (41.8)

19 (4)

Atherosclerotic

Cardioembolic

Unknown

Stroke subtypes

132.9 ± 44.8

11.6 ± 6.0

NIHSS score

15 (29.4)

27 (52.9)

7 (13.7)

79.4 ± 11.8

11 (22.4)

2 (4.1)

12.0 ± 5.6

206 (43.3) 334 (70.2)

19 (37.3) 37 (72.5)

3 (5.9)

5 (9.8)

14 (27.5)

8 (15.7)

4 (7.8) 15 (29.4)

35 (68.6)

26 (51)

65.3 ± 11.0

176.8 ± 55.9

26 (51) 9 (17.6)

70.6 ± 12.7

Midnight–6 AM (00:00–05:59 h) n = 51

Pre-stroke antiplatelet Pre-stroke antihypertensive

Baseline data

69 (14.5)

135 (28.4)

Atrial fibrillation

79 (16.6) 170 (35.7)

Diabetes mellitus Hypercholesterolemia

Current smoking

326 (68.5)

Hypertension

Vascular risk factors

177.3 ± 53.1

OTT time for IV Alteplase

71.2 ± 12.16

263 (55.3) 63 (13.2)

Sex, males Pre-stroke Mrs score [ 0

Age, years

Demographic

All patients n = 476

48 (41.4)

49 (42.2)

18 (15.4)

80.0 ± 11.3

150.0 ± 19.7

135.6 ± 39.0

21 (19.8)

4 (3.7)

13.2 ± 6.3

57 (49.1) 88 (75.9)

9 (7.8)

8 (6.9)

36 (31)

16 (13.8)

21 (18.1) 40 (34.5)

84 (72.4)

62 (53.4)

67.1 ± 11.5

174.7 ± 49.2

63 (54.3) 16 (13.8)

73.2 ± 10.9

6 AM–Noon (06:00–11:59 h) n = 116

Interval for time of Alteplase IV infusion

Table 1 Clinical characteristics of the patients

0.167

0.239

0.483

0.771

0.310

0.702

0.831

0.609

0.218

0.179 0.700

0.473

0.539

0.716

0.812

0.103 0.594

0.711

0.867

0.348

0.810

0.738 0.638

0.184

p value

48 (29.8)

64 (39.8)

41 (25.5)

81.2 ± 12.2

151.6 ± 20.6

130.4 ± 49.2

27 (18.2)

6 (3.9)

10.8 ± 5.5

72 (44.7) 111 (68.9)

11 (6.8)

14 (8.7)

47 (29.2)

24 (14.9)

30 (18.6) 59 (36.6)

107 (66.5)

73 (45.3)

65.5 ± 12.0

176.0 ± 53.6

92 (57.1) 23 (14.3)

70.7 ± 12.5

Noon–6 PM (12:00–17:59 h) n = 161

0.553

0.107

0.087

0.365

0.131

0.741

0.534

0.622

0.211

0.418 0.727

0.554

0.783

0.861

0.524

0.080 0.401

0.865

0.522

0.917

0.928

0.518 0.654

0.948

p value

48 (32.4)

59 (39.9)

33 (22.3)

82.5 ± 12.1

152.1 ± 21.6

132.5 ± 46.9

23 (16.5)

5 (3.6)

11.2 ± 6.1

58 (39.2) 98 (66.2)

2 (1.4)

14 (9.5)

38 (25.7)

21 (14.2)

24 (16.2) 56 (37.8)

100 (67.6)

66 (44.6)

66.6 ± 13.2

180.9 ± 55.0

82 (55.4) 15 (10.1)

70.4 ± 12.4

6 PM–Midnight (18:00–23:59 h) n = 148

0.730

0.140

0.227

0.114

0.113

0.957

0.390

0.588

0.443

0.868 0.488

0.108

0.566

0.854

0.819

0.166 0.313

0.518

0.515

0.545

0.651

0.627 0.210

0.910

p value

Circadian variation in the effect of intravenous thrombolysis 255

123

Results are expressed as number (%), or mean ± standard deviation

mRS modified Rankin Scale, OTT onset to treatment, IV intravenous, NIHSS NIH Stroke Scale, CT cranial tomography, MCA middle cerebral artery, SBP systolic blood pressure, DBP diastolic blood pressure

8 (5.4) 0.553 8 (5) 0.221 1 (0.9) 2 (3.9) 159 (33.4) Other/rare

6 PM–Midnight (18:00–23:59 h) n = 148 p value Noon–6 PM (12:00–17:59 h) n = 161 p value 6 AM–Noon (06:00–11:59 h) n = 116 Midnight–6 AM (00:00–05:59 h) n = 51 All patients n = 476

Interval for time of Alteplase IV infusion Table 1 continued

123

0.504

M. Cappellari et al. p value

256

outcome measures were not different between patients who started IV thrombolysis in the midnight–6 AM interval and other 6-h time intervals (Supplementary Table 1).

Discussion After using the primary outcome measures, our study shows that efficacy of Alteplase IV infusion after nonlacunar stroke in the 6 PM–midnight interval was comparable with the midnight–6 AM interval, but the safety was higher. Compared with the midnight–6 AM interval, IV thrombolysis was less effective from 6 AM to 6 PM, but more safe from noon to 6 PM. After comparison with other 6-h time intervals, from midnight to 6 AM was one of the two intervals more effective, but also one of the two intervals less safe for IV Alteplase infusion. In line with previous studies that reported a circadian distribution of symptoms onset following the 6-h time intervals used in our analyses [1, 2], also the effect of thrombolysis in patients with non-lacunar stroke could show a circadian variation following the same time intervals. Instead, our date on secondary outcome measures are similar to those from previous studies that has not reported a circadian variation in the effect Alteplase IV infusion [6– 8], though the comparison is limited by use of different time blocks based on time of Alteplase IV infusion and inclusion criteria of stroke subtypes. Only a recent study reported controversial data on the relationship between time of Alteplase IV infusion and outcome of patients with middle cerebral artery occlusion. Both the rate of complete recanalization 2 h after thrombolysis and good clinical outcome at 90 days were significantly higher in the group of diurnal (9:00–21:00 h) Alteplase administration compared with those treated in the nocturnal period (21:00–9:00 h). However, this study was limited by sample size and unusual 12-h time intervals [13]. The secondary outcome measures could be less adapted than the primary ones to identify a possible circadian variation in the effect of thrombolysis. Major neurological improvement and hemorrhagic transformation at 24 h could clinically estimate minor variations of efficacy and safety of thrombolysis due to pharmacological properties of Alteplase. The first measure reflects the type of dramatic early improvement that is associated with arterial recanalization [4], and the second includes all types of hemorrhagic transformation, among them also the ones that do not show a neurological deterioration [5]. In addition, the primary outcome measures are not affected by long-term confounding variables, such as patient comorbidities, cognitive abilities, and rehabilitation management. On the basis of a circadian pattern in circulating concentrations of endogenous tissue plasminogen activator

Any ICH at 24 h

1

1

Unadjusted OR (95 % CI)

Any ICH at 24 h

0.69 (0.29–1.62)

0.24 (0.10–0.59)


Any ICH at 24 h

0.26 (0.10–0.67)

0.34 (0.16–0.76)


18/148 (12.2 %)

Any ICH at 24 h

0.20 (0.07–0.57)

0.51 (0.24–1.08)


OR odds ratio, CI confidence interval, ICH intracranial hemorrhage

Results are expressed as the number of events divided by the total number (%), OR (95 % CI)

54/148 (36.5 %)

Major neurological improvement at 24 h

No./total no. (%)

6 PM–Midnight (18:00–23:59 h)

42/161 (26.1 %) 22/161 (13.7 %)


No./total no. (%)

Noon–6 PM (12:00–17:59 h)

27/116 (23.3 %) 28/116 (24.1 %)


No./total no. (%)

6 AM–Noon (06:00–11:59 h)


25/51 (49 %) 14/51 (27.5 %)


No./total no. (%)

Midnight–6 AM (00:00–05:59 h)


0.003

0.082

Unadjusted p value

0.006

0.008

Unadjusted p value

0.389

0.002

Unadjusted p value

–

–

Unadjusted p value

0.26 (0.11–0.62)

0.57 (0.27–1.19)

Adjusted OR (95 % CI)

0.29 (0.12–0.67)

0.40 (0.20–0.81)


0.68 (0.30–1.56)

0.35 (0.16–0.74)


1

1


Table 2 Multivariate analysis: prognostic effect of 6-h time intervals based on time of Alteplase IV infusion on primary outcome measures

0.002

0.134

Adjusted p value

0.004

0.010

Adjusted p value

0.359

0.006

Adjusted p value

–

–

Adjusted p value

Circadian variation in the effect of intravenous thrombolysis 257

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(t-PA), plasminogen activator inhibitor-1, and plasma euglobulin fibrinolytic activity, several clinical and laboratory data reported relatively endogenous pro-fibrinolytic and pro-thrombotic status, respectively during the evening– night and morning hours, when the risk of ischemic stroke is lower and higher [1, 2, 14]. Also, platelet function has a circadian pattern, with greater aggregability in the morning [15]. These endogenous circadian systems may be combined rapidly with the action of Alteplase, which has very rapid clearance (about 15 min after infusion) and short half-life (4–5 min), and produce different results on recanalization success and any symptomatic or asymptomatic hemorrhagic complication, estimated by major neurological improvement and hemorrhagic transformation, respectively. The endogenous pro-fibrinolytic profile may explain why ORs of major neurological improvement were higher in patients who started IV thrombolysis from 6 PM to 6 AM, and OR for hemorrhagic transformation was lower in the 6 PM–midnight interval, compared with midnight– 6 AM interval, when the endogenous pro-fibrinolytic status has not reached the night peak. The same mechanism may explain controversial data on efficacy and safety of IV thrombolysis, when the treatment was started from midnight to 6 AM, after comparison with other time intervals. Our data agree with those from previous studies that reported that the endogenous pro-fibrinolytic condition peaked in this time interval, when the risk of stroke was lower [1, 2, 14]. In addition to circadian pattern, other mechanisms, such as individual predispositions, are needed to explain excellent efficacy in some patients thrombolysed in the midnight–6 AM interval and poor safety in others, compared with other time intervals. Previous studies reported that from 6 AM to noon was the time interval characterized by higher pro-thrombotic condition and risk of stroke [1, 2, 14, 15], but also by higher blood pressure and plasma cortisol-catecholamines levels and risk of hemorrhagic transformation [1, 16, 17]. In line with these data, our findings show that Alteplase IV infusion in this time interval was less effective than midnight–6 AM interval, but ORs for hemorrhagic transformation were comparable. Compared with the midnight–6 AM interval, the noon–6 PM interval was less effective for Alteplase IV infusion, but showed lower risk of hemorrhagic transformation. These data may be explained by relatively orientation of circadian profile in favor of prothrombotic status in this time interval [14, 15]. However, the mechanisms for the circadian pattern of efficacy and safety of IV thrombolysis cannot be determined from this study, and our hypotheses are purely speculative. Further investigation of the mechanisms for these circadian patterns is needed. Potential therapeutic implications of finding circadian variation in the efficacy and safety of IV thrombolysis may

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include: adjustment of rt-PA dose based on time of Alteplase IV infusion and conjunctive use of pharmacological agents, including anticoagulant or antiplatelet agents, during the acute phase of stroke. However, each of which hypotheses would require full investigations. Although there were not intergroup imbalances in baseline characteristics, we are aware of some limitations of our study. First, this is characterized by the inherent weakness of any retrospective study such as collection and entry bias, and possible residual confounding. Also, a weakness of the present study might be the lack of measurement of fibrinolysis and coagulation/antiplatelet aggregation factors before and after thrombolysis; however, this may be investigated only in a prospective study and not in a retrospective observational study.

Conclusion The effect of Alteplase IV infusion could show a circadian variation in patients with non-lacunar stroke. After comparison with the midnight–6 AM interval, IV thrombolysis could be more safe from noon to midnight, and less effective from 6 AM to 6 PM. However, the results of our study should be interpreted with caution and not hinder the use of thrombolysis for stroke in routine clinical practice. The corresponding author takes full responsibility for the data, the analyses and interpretation, and the conduct of the research. The corresponding author has full access to all of the data. All authors have no financial interests to disclose. All authors have seen and agree with the contents of the manuscript and the submission is not under review at any other publication. Conflict of interest The authors have no conflict of interest to declare.

References 1. Elliott WJ (1998) Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 29:992–996 2. Chaturvedi S, Adams HP Jr, Woolson RF (1999) Circadian variation in ischemic stroke subtypes. Stroke 30:1792–1795 3. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41 4. Brown DL, Johnston KC, Wagner DP, Haley EC Jr (2004) Predicting major neurological improvement with intravenous recombinant tissue plasminogen activator treatment of stroke. Stroke 35:147–150 5. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Ho¨xter G, Mahagne MH (1995)

Circadian variation in the effect of intravenous thrombolysis

6.

7.

8.

9.

10.

Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 274:1017–1025 Rhoney DH, Coplin WM, Lin Y, Frankel M, Lyden PD, Levine SR (2010) Time of day, outcome, and response to thrombolytic therapy: the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Trial experience. J Stroke Cerebrovasc Dis 19:40–48 Helsinki Stroke Thrombolysis Registry Group (2012) Does time of day or physician experience affect outcome of acute ischemic stroke patients treated with thrombolysis? A study from Finland. Int J Stroke 7:511–516 Ko˜rv J, Vibo R, Kadlecova´ P, Kobayashi A, Czlonkowska A, Brozman M, Svigelj V, Csiba L, Fekete K, Demarin V, Vilionskis A, Jatuzis D, Krespi Y, Ahmed N, Mikulı´k R (2013) For the Safe Implementation of Treatments in Stroke–East (SITS-EAST) Registry Investigators. Benefit of thrombolysis for stroke is maintained around the clock: results from the SITS-EAST Registry. Eur J Neurol. doi:10.1111/ene.12257 National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581–1587 Wahlgren N, Ahmed N, Da´valos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G (2007) SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-

259

11.

12.

13.

14. 15.

16. 17.

monitoring study (SITS-MOST): an observational study. Lancet 369:275–282 Hacke W, Kaste M, Bluhmki E, Brozman M, Da´valos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D (2008) ECASS investigators. Thrombolysis with alteplase 3–4.5 h after acute ischemic stroke. N Engl J Med 359:1317–1329 Gensicke H, Seiffge DJ, Polasek AE, Peters N, Bonati LH, Lyrer PA, Engelter ST (2013) Long-term outcome in stroke patients treated with IV thrombolysis. Neurology 80:919–925 Vilas D, Gomis M, Blanco M, Corte´s J, Milla´n M, de la Pe´rez Ossa N, Dorado L, Lo´pez-Cancio E, Sun˜ol A, Da´valos A (2012) Circadian rhythms in the efficacy of intravenous alteplase in patients with acute ischemic stroke and middle cerebral artery occlusion. Chronobiol Int 29(10):1383–1389 Grimaudo V, Hauert J, Bachmann F, Kruithof EK (1988) Diurnal variation of the fibrinolytic system. Thromb Haemost 59:495–499 Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE (1987) Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 316:1514–1518 Millar-Craig MW, Bishop CN, Raftery EB (1978) Circadian variation of blood pressure. Lancet 1:745–747 Turton MB, Deegan T (1974) Circadian variations of plasma catecholamine, cortisol, and immunoreactive insulin concentrations in supine subjects. Clin Chim Ada 55:389–397

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