Skip to main content
SpringerLink
Log in

Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Objective

To investigate the safety and efficacy of intensive statin in the acute phase of ischemic stroke after intravenous thrombolysis therapy.

Methods

A total of 310 stroke patients treated with rt-PA were randomly scheduled into the intensive statin group (rosuvastatin 20 mg daily × 14 days) and the control group (rosuvastatin 5 mg daily × 14 days). The primary clinical endpoint was excellent functional outcome (mRS ≤ 1) at 3 months, and the primary safety endpoint was symptomatic intracranial hemorrhage (sICH) in 90 days.

Results

The intensive statin users did not achieve a favorable outcome in excellent functional outcome (mRS ≤ 1) at 3 months compared with controls (70.3% vs. 66.5%, p = 0.464). Intensive statin also not significantly improved the overall distribution of scores on the modified Rankin scale, as compared with controls (p = 0.82 by the Cochran–Mantel–Haenszel test). The incidence of primary safety endpoint events (sICH) in 90 days did not significantly differ between the intensive statin group and control group (0.6% vs. 1.3%, p > 0.999).

Conclusion

The INSPIRE study indicated that intensive statin therapy may not improve clinical outcomes compared with the low dose of statin therapy in AIS patients undergoing intravenous thrombolysis, and the two groups had similar safety profile.

Clinical trial registration

URL: http://www.chictr.org. Unique identifier: ChiCTR-IPR-16008642

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All the data of the INSPIRE trial were included in the article and Online Resource document. The raw data of this trial are available from the corresponding author for reasonable request.

Abbreviations

INSPIRE:

Intensive statin plus intravenous rtPA in acute ischemic stroke

sICH:

Symptomatic intracranial hemorrhage

AIS:

Acute ischemic stroke

rt-PA:

Recombinant tissue plasminogen activator

ULN:

Upper limit of normal

IV:

Intravenous

mRS:

Modified Rankin scale

References

  1. Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T, O’Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C (2014) Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet (London, England) 383(9913):245–254. https://doi.org/10.1016/s0140-6736(13)61953-4

    Article  Google Scholar 

  2. Furie KL, Jayaraman MV (2018) 2018 Guidelines for the early management of patients with acute ischemic stroke. Stroke 49(3):509–510. https://doi.org/10.1161/strokeaha.118.020176

    Article  PubMed  Google Scholar 

  3. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H (2013) Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44(3):870–947. https://doi.org/10.1161/STR.0b013e318284056a

    Article  PubMed  Google Scholar 

  4. Xu AD, Wang YJ, Wang DZ (2013) Consensus statement on the use of intravenous recombinant tissue plasminogen activator to treat acute ischemic stroke by the Chinese Stroke Therapy Expert Panel. CNS Neurosci Ther 19(8):543–548. https://doi.org/10.1111/cns.12126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, Brott T, Cohen G, Davis S, Donnan G, Grotta J, Howard G, Kaste M, Koga M, von Kummer R, Lansberg M, Lindley RI, Murray G, Olivot JM, Parsons M, Tilley B, Toni D, Toyoda K, Wahlgren N, Wardlaw J, Whiteley W, del Zoppo GJ, Baigent C, Sandercock P, Hacke W (2014) Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet (London, England) 384(9958):1929–1935. https://doi.org/10.1016/s0140-6736(14)60584-5

    Article  CAS  Google Scholar 

  6. Martí-Fàbregas J, Bravo Y, Cocho D, Martí-Vilalta JL, Díaz-Manera J, San Román L, Puig M, Blanco M, Castellanos M, Millán M, Roquer J, Obach V, Maestre J (2007) Frequency and predictors of symptomatic intracerebral hemorrhage in patients with ischemic stroke treated with recombinant tissue plasminogen activator outside clinical trials. Cerebrovasc Dis (Basel, Switzerland) 23(2–3):85–90. https://doi.org/10.1159/000097043

    Article  CAS  Google Scholar 

  7. Wahlgren N, Ahmed N, Dávalos 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) Thrombolysis with alteplase for acute ischaemic stroke in the safe implementation of thrombolysis in stroke-monitoring study (SITS-MOST): an observational study. Lancet (London, England) 369(9558):275–282. https://doi.org/10.1016/s0140-6736(07)60149-4

    Article  CAS  Google Scholar 

  8. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Engl J Med 352(14):1425–1435. https://doi.org/10.1056/NEJMoa050461

    Article  CAS  PubMed  Google Scholar 

  9. Nc D, Callaly EL, Duggan J, Merwick Á, Hannon N, Sheehan Ó, Marnane M, Horgan G, Williams EB, Harris D, Kyne L, McCormack PM, Moroney J, Grant T, Williams D, Daly L, Kelly PJ (2011) Association between acute statin therapy, survival, and improved functional outcome after ischemic stroke: the North Dublin Population Stroke Study. Stroke 42(4):1021–1029. https://doi.org/10.1161/strokeaha.110.596734

    Article  Google Scholar 

  10. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, Zivin JA (2006) High-dose atorvastatin after stroke or transient ischemic attack. New Engl J Med 355(6):549–559. https://doi.org/10.1056/NEJMoa061894

    Article  CAS  PubMed  Google Scholar 

  11. Scheitz JF, Seiffge DJ, Tutuncu S, Gensicke H, Audebert HJ, Bonati LH, Fiebach JB, Tranka C, Lyrer PA, Endres M, Engelter ST, Nolte CH (2014) Dose-related effects of statins on symptomatic intracerebral hemorrhage and outcome after thrombolysis for ischemic stroke. Stroke 45(2):509–514. https://doi.org/10.1161/strokeaha.113.002751

    Article  CAS  PubMed  Google Scholar 

  12. Alvarez-Sabin J, Huertas R, Quintana M, Rubiera M, Delgado P, Ribo M, Molina CA, Montaner J (2007) Prior statin use may be associated with improved stroke outcome after tissue plasminogen activator. Stroke 38(3):1076–1078. https://doi.org/10.1161/01.STR.0000258075.58283.8f

    Article  CAS  PubMed  Google Scholar 

  13. Uyttenboogaart M, Koch MW, Koopman K, Vroomen PC, Luijckx GJ, De Keyser J (2008) Lipid profile, statin use, and outcome after intravenous thrombolysis for acute ischaemic stroke. J Neurol 255(6):875–880. https://doi.org/10.1007/s00415-008-0797-7

    Article  CAS  PubMed  Google Scholar 

  14. Miedema I, Uyttenboogaart M, Koopman K, De Keyser J, Luijckx GJ (2010) Statin use and functional outcome after tissue plasminogen activator treatment in acute ischaemic stroke. Cerebrovasc Dis (Basel, Switzerland) 29(3):263–267. https://doi.org/10.1159/000275500

    Article  CAS  Google Scholar 

  15. Martinez-Ramirez S, Delgado-Mederos R, Marin R, Suarez-Calvet M, Sainz MP, Alejaldre A, Vidal-Jordana A, Marti-Vilalta JL, Marti-Fabregas J (2012) Statin pretreatment may increase the risk of symptomatic intracranial haemorrhage in thrombolysis for ischemic stroke: results from a case-control study and a meta-analysis. J Neurol 259(1):111–118. https://doi.org/10.1007/s00415-011-6137-3

    Article  CAS  PubMed  Google Scholar 

  16. Giroud M, Creisson E, Fayolle H, Andre N, Becker F, Martin D, Dumas R (1995) Risk factors for primary cerebral hemorrhage: a population-based study—the Stroke Registry of Dijon. Neuroepidemiology 14(1):20–26. https://doi.org/10.1159/000109775

    Article  CAS  PubMed  Google Scholar 

  17. Cappellari M, Deluca C, Tinazzi M, Tomelleri G, Carletti M, Fiaschi A, Bovi P, Moretto G (2011) Does statin in the acute phase of ischemic stroke improve outcome after intravenous thrombolysis? A retrospective study. J Neurol Sci 308(1–2):128–134. https://doi.org/10.1016/j.jns.2011.05.026

    Article  CAS  PubMed  Google Scholar 

  18. Cappellari M, Bovi P, Moretto G, Zini A, Nencini P, Sessa M, Furlan M, Pezzini A, Orlandi G, Paciaroni M, Tassinari T, Procaccianti G, Di Lazzaro V, Bettoni L, Gandolfo C, Silvestrelli G, Rasura M, Martini G, Melis M, Calloni MV, Chiodo-Grandi F, Beretta S, Guarino M, Altavista MC, Marcheselli S, Galletti G, Adobbati L, Del Sette M, Mancini A, Orrico D, Monaco S, Cavallini A, Sciolla R, Federico F, Scoditti U, Brusaferri F, Grassa C, Specchio L, Bongioanni MR, Sparaco M, Zampolini M, Greco G, Colombo R, Passarella B, Adami A, Consoli D, Toni D (2013) The thrombolysis and statins (THRaST) study. Neurology 80(7):655–661. https://doi.org/10.1212/WNL.0b013e318281cc83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Geng J, Song Y, Mu Z, Xu Q, Shi G, Sun Y, Chen Y, Lin Y, Pan Y, Yu L, Yang GY, Li Y (2016) Early use of statin in patients treated with alteplase for acute ischemic stroke. Acta Neurochir Suppl 121:269–275. https://doi.org/10.1007/978-3-319-18497-5_47

    Article  PubMed  Google Scholar 

  20. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P (1998) Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet (London, England) 352(9136):1245–1251. https://doi.org/10.1016/s0140-6736(98)08020-9

    Article  CAS  Google Scholar 

  21. Allen LM, Hasso AN, Handwerker J, Farid H (2012) Sequence-specific MR imaging findings that are useful in dating ischemic stroke. Radiographics 32(5):1285–1297; discussion 1297–1289. https://doi.org/10.1148/rg.325115760

  22. Šimić I, Reiner Ž (2015) Adverse effects of statins—myths and reality. Curr Pharm Des 21(9):1220–1226. https://doi.org/10.2174/1381612820666141013134447

    Article  CAS  PubMed  Google Scholar 

  23. Lu D, Liu Y, Mai H, Zang J, Shen L, Zhang Y, Xu A (2018) Rosuvastatin reduces neuroinflammation in the hemorrhagic transformation after rt-PA treatment in a mouse model of experimental stroke. Front Cell Neurosci 12:225. https://doi.org/10.3389/fncel.2018.00225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kelly P, Prabhakaran S (2017) Statins for neuroprotection after acute ischemic stroke: assorted results but more trials needed. Stroke 48(11):2922–2923. https://doi.org/10.1161/strokeaha.117.018725

    Article  PubMed  Google Scholar 

  25. Nc D, Asplund K, Åsberg S, Callaly E, Cuadrado-Godia E, Díez-Tejedor E, Di Napoli M, Engelter ST, Furie KL, Giannopoulos S, Gotto AM Jr, Hannon N, Jonsson F, Kapral MK, Martí-Fàbregas J, Martínez-Sánchez P, Milionis HJ, Montaner J, Muscari A, Pikija S, Probstfield J, Rost NS, Thrift AG, Vemmos K, Kelly PJ (2013) Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke 44(2):448–456. https://doi.org/10.1161/strokeaha.112.668277

    Article  Google Scholar 

  26. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL (2018) 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals From the American Heart Association/American Stroke Association. Stroke 49(3):e46–e110. https://doi.org/10.1161/str.0000000000000158

    Article  PubMed  Google Scholar 

  27. Engelter ST, Soinne L, Ringleb P, Sarikaya H, Bordet R, Berrouschot J, Odier C, Arnold M, Ford GA, Pezzini A, Zini A, Rantanen K, Rocco A, Bonati LH, Kellert L, Strbian D, Stoll A, Meier N, Michel P, Baumgartner RW, Leys D, Tatlisumak T, Lyrer PA (2011) IV thrombolysis and statins. Neurology 77(9):888–895. https://doi.org/10.1212/WNL.0b013e31822c9135

    Article  CAS  PubMed  Google Scholar 

  28. Hong KS, Lee JS (2015) Statins in acute ischemic stroke: a systematic review. Journal of stroke 17(3):282–301. https://doi.org/10.5853/jos.2015.17.3.282

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bourcier T, Libby P (2000) HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol 20(2):556–562

    Article  CAS  Google Scholar 

  30. Sanguigni V, Pignatelli P, Lenti L, Ferro D, Bellia A, Carnevale R, Tesauro M, Sorge R, Lauro R, Violi F (2005) Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 111(4):412–419. https://doi.org/10.1161/01.cir.0000153810.81187.7d

    Article  CAS  PubMed  Google Scholar 

  31. Notarbartolo A, Davi G, Averna M, Barbagallo CM, Ganci A, Giammarresi C, La Placa FP, Patrono C (1995) Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb Vasc Biol 15(2):247–251

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the staffs of the Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University and Clinical Neuroscience Institute of Jinan University, China.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81171084, 81671167, and 81801150), the Guangzhou Science and Technology Program of China (No. 2014Y2-00505), the Science and Technology Program of Guangdong, China (No. 2014A030313384, 201508020004 and 2017A020215049), Guangdong Natural Science Foundation (2018A0303130182).

Author information

Author notes

  1. Wan-Yong Yang and Yu-Feng Li contributed to the work equally and should be regarded as co-first author.

Authors and Affiliations

  1. Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China

    Wan-Yong Yang, Yu-Feng Li, Li-An Huang, Yu-Sheng Zhang, Ze-Feng Tan, Dan Lu, Niu He, Da-Wei Dong, Hui-Li Zhu, Bing Yang & An-Ding Xu

  2. Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, 510630, China

    Wan-Yong Yang, Yu-Feng Li, Li-An Huang, Yu-Sheng Zhang, Ze-Feng Tan, Dan Lu, Niu He, Da-Wei Dong, Hui-Li Zhu, Bing Yang & An-Ding Xu

  3. Department of Neurology, Sun-Yet Sen Memorial Hospital of Sun-Yet Sen University, Guangzhou, 510120, China

    Qing-Yu Shen

  4. Department of Neurology and Stroke Center, Linyi People’s Hospital, Linyi, 276003, China

    Zi-Ran Wang

  5. Department of Neurology, Yan Tai Shan Hospital, Yantai, 264000, China

    Tian-Xia Yu

  6. Department of Neurology, Dongyang Affiliated Hospital of Wenzhou Medical University, Dongyang, 322100, China

    Dong-Juan Xu

  7. Department of Neurology, Traditional Chinese Medicine Hospital of Zhongshan City, Zhongshan, 528400, China

    Nan Yang

  8. Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030000, China

    Xiao-Yuan Niu

  9. Department of Biostatistics, School of Public Health, Southern Medical University, Guangzhou, 510515, China

    Ying Guan

  10. Department of Neurology, Lishui Hospital of Zhejiang University, The Central Hospital of Lishui, Lishui, 323000, China

    Xue-Li Cai

  11. Department of Neurology, Zhuhai Hospital Affiliated With Jinan University, Zhuhai, 519000, China

    Wen-Yan Zhuo

  12. Department of Neurology, General Hospital of TISCO, Taiyuan, 030000, China

    Xue-Mei Wu

  13. Jingdong Medical District, General Hospital of the Chinese People’s Liberation Army, Beijing, 100853, China

    Min Yan

  14. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210000, China

    Jun-Shan Zhou

  15. Department of Neurology, Laixi City People’s Hospital, Qingdao, 266600, China

    Hao-Wen Zhang

  16. Department of Neurology, Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, China

    Zhi-Gang Liang

  17. Department of Neurology, Zhongshan City People’s Hospital, Zhongshan, 528403, China

    Wen-Jun Wu

  18. Department of Neurology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Jian-Hua Cheng

Authors
  1. Wan-Yong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zi-Ran Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tian-Xia Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dong-Juan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Yuan Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xue-Li Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wen-Yan Zhuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xue-Mei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Min Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jun-Shan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hao-Wen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Zhi-Gang Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Wen-Jun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jian-Hua Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Li-An Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yu-Sheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Ying Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Ze-Feng Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Dan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Niu He
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Da-Wei Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Hui-Li Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Bing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Qing-Yu Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. An-Ding Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

An-Ding Xu, Qing-Yu Shen, Wan-Yong Yang and Yu-Feng Li contributed to the study conception and design. Material preparation and data collection were performed by Zi-Ran Wang, Tian-Xia Yu, Dong-Juan Xu, Nan Yang, Xiao-Yuan Niu, Li-An Huang, Yu-Sheng Zhang, Dan Lu, Ying Guan, Ze-Feng Tan, Hui-Li Zhu, Bing Yang, Da-Wei Dong, Niu He, Xue-Li Cai, Wen-Yan Zhuo, Xue-Mei Wu, Min Yan, Jun-Shan Zhou, Hao-Wen Zhang, Zhi-Gang Liang, Wen-Jun Wu, Jian-Hua Cheng. Analysis and interpretation of the data were done by Ying Guan and Yu-Feng Li. The first draft of the manuscript was written by Yu-Feng Li, and An-Ding Xu, Wan-Yong Yang and Ze-Feng Tan commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Qing-Yu Shen or An-Ding Xu.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to disclose.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file 1 (DOCX 52 KB)

Supplementary file 2 (DOCX 188 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, WY., Li, YF., Wang, ZR. et al. Combined therapy of intensive statin plus intravenous rt-PA in acute ischemic stroke: the INSPIRE randomized clinical trial. J Neurol 268, 2560–2569 (2021). https://doi.org/10.1007/s00415-020-10388-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-020-10388-3

Keywords

Search

Navigation