Advertisement

Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials

  • Konark Malhotra
  • Jason J. Chang
  • Arjun Khunger
  • David Blacker
  • Jeffrey A. Switzer
  • Nitin Goyal
  • Adrian V. Hernandez
  • Vinay Pasupuleti
  • Andrei V. Alexandrov
  • Georgios Tsivgoulis
Original Communication

Abstract

Background

Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke.

Methods

Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models.

Results

We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion.

Conclusions

Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients.

Keywords

Minocycline Ischemic stroke Intracerebral hemorrhage Recovery 

Notes

Author contributions

KM: Study concept and design, acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. JJC: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. AK: Analysis and interpretation, critical revision of the manuscript for important intellectual content. DB: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. JAS: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. NG: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. AVH: Analysis and interpretation, critical revision of the manuscript for important intellectual content. VP: Analysis and interpretation, critical revision of the manuscript for important intellectual content. AVA: Acquisition and interpretation of data, critical revision of the manuscript for important intellectual content. GT: Study concept and design, study supervision, critical revision of the manuscript for important intellectual content.

Funding

This study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Compliance with ethical standards

Conflicts of interest

Dr. Malhotra reports no disclosures. Dr. Chang reports no disclosures. Dr. Khunger reports no disclosures. Dr. Blacker reports no disclosures. Dr. Switzer reports no disclosures. Dr. Goyal reports no disclosures. Dr. Hernandez reports no disclosures. Dr. Pasupuleti reports no disclosures. Dr. Alexandrov reports no disclosures. Dr. Tsivgoulis reports no disclosures.

Supplementary material

415_2018_8935_MOESM1_ESM.doc (844 kb)
Supplementary material 1 (DOC 844 KB)

References

  1. 1.
    Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417(6884):74–78.  https://doi.org/10.1038/417074a CrossRefPubMedGoogle Scholar
  2. 2.
    Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51(2):215–223CrossRefPubMedGoogle Scholar
  3. 3.
    Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW (2002) Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain: J Neurol 125(Pt 6):1297–1308CrossRefGoogle Scholar
  4. 4.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med 6(7):797–801.  https://doi.org/10.1038/77528 CrossRefPubMedGoogle Scholar
  5. 5.
    Fan X, Lo EH, Wang X (2013) Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats. Stroke; J Cereb Circ 44(3):745–752.  https://doi.org/10.1161/strokeaha.111.000309 CrossRefGoogle Scholar
  6. 6.
    Soliman S, Ishrat T, Fouda AY, Patel A, Pillai B, Fagan SC (2015) Sequential therapy with minocycline and candesartan improves long-term recovery after experimental stroke. Transl Stroke Res 6(4):309–322.  https://doi.org/10.1007/s12975-015-0408-8 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, Hess DC, Waller JL, Fagan SC (2009) Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke 40(9):3028–3033.  https://doi.org/10.1161/strokeaha.109.556852 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH (2008) Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke 39(12):3372–3377.  https://doi.org/10.1161/strokeaha.108.514026 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Kohler E, Prentice DA, Bates TR, Hankey GJ, Claxton A, van Heerden J, Blacker D (2013) Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis. Stroke 44(9):2493–2499.  https://doi.org/10.1161/strokeaha.113.000780 CrossRefPubMedGoogle Scholar
  10. 10.
    Chang JJ, Kim-Tenser M, Emanuel BA, Jones GM, Chapple K, Alikhani A, Sanossian N, Mack WJ, Tsivgoulis G, Alexandrov AV, Pourmotabbed T (2017) Minocycline and matrix metalloproteinase inhibition in acute intracerebral hemorrhage: a pilot study. Eur J Neurol 24(11):1384–1391.  https://doi.org/10.1111/ene.13403 CrossRefPubMedGoogle Scholar
  11. 11.
    Fouda AY, Newsome AS, Spellicy S, Waller JL, Zhi W, Hess DC, Ergul A, Edwards DJ, Fagan SC, Switzer JA (2017) Minocycline in acute cerebral hemorrhage: an early phase randomized trial. Stroke 48(10):2885–2887.  https://doi.org/10.1161/strokeaha.117.018658 CrossRefPubMedGoogle Scholar
  12. 12.
    Blacker DJ, Prentice D, Alvaro A, Bates TR, Bynevelt M, Kelly A, Kho LK, Kohler E, Hankey GJ, Thompson A, Major T (2013) Reducing haemorrhagic transformation after thrombolysis for stroke: a strategy utilising minocycline. Stroke Res Treat 2013:362961.  https://doi.org/10.1155/2013/362961 PubMedPubMedCentralGoogle Scholar
  13. 13.
    Amiri-Nikpour MR, Nazarbaghi S, Hamdi-Holasou M, Rezaei Y (2015) An open-label evaluator-blinded clinical study of minocycline neuroprotection in ischemic stroke: gender-dependent effect. Acta Neurol Scand 131(1):45–50.  https://doi.org/10.1111/ane.12296 CrossRefPubMedGoogle Scholar
  14. 14.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188CrossRefPubMedGoogle Scholar
  15. 15.
    Sweeting MJ, Sutton AJ, Lambert PC (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23(9):1351–1375.  https://doi.org/10.1002/sim.1761 CrossRefPubMedGoogle Scholar
  16. 16.
    Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions, vol 4. Wiley, ChichesterGoogle Scholar
  17. 17.
    Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, Carpenter J, Rücker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JPT (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ.  https://doi.org/10.1136/bmj.d4002 PubMedCentralGoogle Scholar
  18. 18.
    Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53(11):1119–1129CrossRefPubMedGoogle Scholar
  19. 19.
    Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, Pettigrew LC, Clark WM, Fagan SC (2011) Matrix metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 42(9):2633–2635.  https://doi.org/10.1161/strokeaha.111.618215 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC (2010) Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 41(10):2283–2287.  https://doi.org/10.1161/strokeaha.110.582601 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69(14):1404–1410.  https://doi.org/10.1212/01.wnl.0000277487.04281.db CrossRefPubMedGoogle Scholar
  22. 22.
    Padma Srivastava MV, Bhasin A, Bhatia R, Garg A, Gaikwad S, Prasad K, Singh MB, Tripathi M (2012) Efficacy of minocycline in acute ischemic stroke: a single-blinded, placebo-controlled trial. Neurol India 60(1):23–28CrossRefPubMedGoogle Scholar
  23. 23.
    Barr TL, Latour LL, Lee KY, Schaewe TJ, Luby M, Chang GS, El-Zammar Z, Alam S, Hallenbeck JM, Kidwell CS, Warach S (2010) Blood-brain barrier disruption in humans is independently associated with increased matrix metalloproteinase-9. Stroke 41(3):e123–e128.  https://doi.org/10.1161/strokeaha.109.570515 CrossRefGoogle Scholar
  24. 24.
    Li N, Liu YF, Ma L, Worthmann H, Wang YL, Wang YJ, Gao YP, Raab P, Dengler R, Weissenborn K, Zhao XQ (2013) Association of molecular markers with perihematomal edema and clinical outcome in intracerebral hemorrhage. Stroke 44(3):658–663.  https://doi.org/10.1161/strokeaha.112.673590 CrossRefPubMedGoogle Scholar
  25. 25.
    Castellazzi M, Tamborino C, De Santis G, Garofano F, Lupato A, Ramponi V, Trentini A, Casetta I, Bellini T, Fainardi E (2010) Timing of serum active MMP-9 and MMP-2 levels in acute and subacute phases after spontaneous intracerebral hemorrhage. Acta Neurochir Suppl 106:137–140.  https://doi.org/10.1007/978-3-211-98811-4_24 CrossRefPubMedGoogle Scholar
  26. 26.
    Alvarez-Sabin J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribo M, Santamarina E, Quintana M, Monasterio J, Montaner J (2004) Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 35(6):1316–1322.  https://doi.org/10.1161/01.str.0000126827.69286.90 CrossRefPubMedGoogle Scholar
  27. 27.
    Wu J, Yang S, Hua Y, Liu W, Keep RF, Xi G (2010) Minocycline attenuates brain edema, brain atrophy and neurological deficits after intracerebral hemorrhage. Acta Neurochir Suppl 106:147–150.  https://doi.org/10.1007/978-3-211-98811-4_26 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Konark Malhotra
    • 1
  • Jason J. Chang
    • 2
  • Arjun Khunger
    • 3
  • David Blacker
    • 4
  • Jeffrey A. Switzer
    • 5
  • Nitin Goyal
    • 6
  • Adrian V. Hernandez
    • 7
    • 8
  • Vinay Pasupuleti
    • 9
  • Andrei V. Alexandrov
    • 6
  • Georgios Tsivgoulis
    • 6
    • 10
  1. 1.Department of Neurology, Charleston Area Medical CenterWest Virginia University-Charleston DivisionCharlestonUSA
  2. 2.Department of Critical Care MedicineMedStar Washington Hospital CenterWashington, DCUSA
  3. 3.Department of Hematology and Oncology, Cleveland Clinic FoundationClevelandUSA
  4. 4.Department of Neurology and Clinical NeurophysiologySir Charles Gairdner HospitalNedlandsAustralia
  5. 5.Department of NeurologyMedical College of Georgia at Augusta UniversityGeorgiaUSA
  6. 6.Department of NeurologyUniversity of Tennessee Health Science CenterMemphisUSA
  7. 7.University of Connecticut/Hartford Hospital Evidence-based Practice CenterHartfordUSA
  8. 8.School of MedicineUniversidad Peruana de Ciencias Aplicadas (UPC)LimaPeru
  9. 9.ProEd Communications Inc.ClevelandUSA
  10. 10.Second Department of NeurologyNational and Kapodistrian University of Athens, “Attikon” University HospitalAthensGreece

Personalised recommendations