Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials
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.
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.
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 Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs.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.
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.
KeywordsMinocycline Ischemic stroke Intracerebral hemorrhage Recovery
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.
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.
- 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
- 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
- 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
- 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
- 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
- 16.Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions, vol 4. Wiley, ChichesterGoogle Scholar
- 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
- 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.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.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
- 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.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.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.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