Meta-Analysis

. 2019 Apr 30;92(18):e2150-e2164.

doi: 10.1212/WNL.0000000000007397. Epub 2019 Apr 5.

Haptoglobin genotype and aneurysmal subarachnoid hemorrhage: Individual patient data analysis

Ben Gaastra¹, Dianxu Ren¹, Sheila Alexander¹, Ellen R Bennett¹, Dawn M Bielawski¹, Spiros L Blackburn¹, Mark K Borsody¹, Sylvain Doré¹, James Galea¹, Patrick Garland¹, Tian He¹, Koji Iihara¹, Yoichiro Kawamura¹, Jenna L Leclerc¹, James F Meschia¹, Michael A Pizzi¹, Rafael J Tamargo¹, Wuyang Yang¹, Paul A Nyquist¹, Diederik O Bulters¹, Ian Galea²

Affiliations

¹ From the Wessex Neurological Centre (B.G., D.O.B., I.G.), University Hospital Southampton NHS Foundation Trust, UK; School of Nursing (D.R., S.A.) and Department of Biostatistics (D.R., T.E.), University of Pittsburgh, PA; Department of Neurology (E.R.B.), Duke University School of Medicine, Durham, NC; NeuroSpring (D.M.B., M.K.B.), Dover, DE; Department of Neurosurgery (S.L.B.), University of Texas Health Science Center at Houston; Department of Anesthesiology, Neurology, Psychiatry, Psychology, Pharmaceutics, and Neuroscience (S.D., J.L.L.), College of Medicine, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville; Brain Injury Research Group (J.G.), Division of Cardiovascular Sciences (University of Manchester), Salford Royal NHS Foundation Trust, UK; Clinical Neurosciences, Clinical & Experimental Sciences (P.G., I.G.), Faculty of Medicine, University of Southampton, UK; Department of Neurosurgery (K.I., Y.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology (J.F.M., M.A.P.), Mayo Clinic, Jacksonville, FL; and Division of Cerebrovascular Neurosurgery (R.J.T.) and Departments of Neurology, Anesthesia/Critical Care Medicine, and Neurosurgery (W.Y., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
² From the Wessex Neurological Centre (B.G., D.O.B., I.G.), University Hospital Southampton NHS Foundation Trust, UK; School of Nursing (D.R., S.A.) and Department of Biostatistics (D.R., T.E.), University of Pittsburgh, PA; Department of Neurology (E.R.B.), Duke University School of Medicine, Durham, NC; NeuroSpring (D.M.B., M.K.B.), Dover, DE; Department of Neurosurgery (S.L.B.), University of Texas Health Science Center at Houston; Department of Anesthesiology, Neurology, Psychiatry, Psychology, Pharmaceutics, and Neuroscience (S.D., J.L.L.), College of Medicine, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville; Brain Injury Research Group (J.G.), Division of Cardiovascular Sciences (University of Manchester), Salford Royal NHS Foundation Trust, UK; Clinical Neurosciences, Clinical & Experimental Sciences (P.G., I.G.), Faculty of Medicine, University of Southampton, UK; Department of Neurosurgery (K.I., Y.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology (J.F.M., M.A.P.), Mayo Clinic, Jacksonville, FL; and Division of Cerebrovascular Neurosurgery (R.J.T.) and Departments of Neurology, Anesthesia/Critical Care Medicine, and Neurosurgery (W.Y., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD. I.Galea@soton.ac.uk.

PMID: 30952792
PMCID: PMC6512887
DOI: 10.1212/WNL.0000000000007397

Meta-Analysis

Haptoglobin genotype and aneurysmal subarachnoid hemorrhage: Individual patient data analysis

Ben Gaastra et al. Neurology. 2019.

. 2019 Apr 30;92(18):e2150-e2164.

doi: 10.1212/WNL.0000000000007397. Epub 2019 Apr 5.

Authors

Affiliations

¹ From the Wessex Neurological Centre (B.G., D.O.B., I.G.), University Hospital Southampton NHS Foundation Trust, UK; School of Nursing (D.R., S.A.) and Department of Biostatistics (D.R., T.E.), University of Pittsburgh, PA; Department of Neurology (E.R.B.), Duke University School of Medicine, Durham, NC; NeuroSpring (D.M.B., M.K.B.), Dover, DE; Department of Neurosurgery (S.L.B.), University of Texas Health Science Center at Houston; Department of Anesthesiology, Neurology, Psychiatry, Psychology, Pharmaceutics, and Neuroscience (S.D., J.L.L.), College of Medicine, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville; Brain Injury Research Group (J.G.), Division of Cardiovascular Sciences (University of Manchester), Salford Royal NHS Foundation Trust, UK; Clinical Neurosciences, Clinical & Experimental Sciences (P.G., I.G.), Faculty of Medicine, University of Southampton, UK; Department of Neurosurgery (K.I., Y.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology (J.F.M., M.A.P.), Mayo Clinic, Jacksonville, FL; and Division of Cerebrovascular Neurosurgery (R.J.T.) and Departments of Neurology, Anesthesia/Critical Care Medicine, and Neurosurgery (W.Y., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD.
² From the Wessex Neurological Centre (B.G., D.O.B., I.G.), University Hospital Southampton NHS Foundation Trust, UK; School of Nursing (D.R., S.A.) and Department of Biostatistics (D.R., T.E.), University of Pittsburgh, PA; Department of Neurology (E.R.B.), Duke University School of Medicine, Durham, NC; NeuroSpring (D.M.B., M.K.B.), Dover, DE; Department of Neurosurgery (S.L.B.), University of Texas Health Science Center at Houston; Department of Anesthesiology, Neurology, Psychiatry, Psychology, Pharmaceutics, and Neuroscience (S.D., J.L.L.), College of Medicine, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, Gainesville; Brain Injury Research Group (J.G.), Division of Cardiovascular Sciences (University of Manchester), Salford Royal NHS Foundation Trust, UK; Clinical Neurosciences, Clinical & Experimental Sciences (P.G., I.G.), Faculty of Medicine, University of Southampton, UK; Department of Neurosurgery (K.I., Y.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology (J.F.M., M.A.P.), Mayo Clinic, Jacksonville, FL; and Division of Cerebrovascular Neurosurgery (R.J.T.) and Departments of Neurology, Anesthesia/Critical Care Medicine, and Neurosurgery (W.Y., P.A.N.), Johns Hopkins University School of Medicine, Baltimore, MD. I.Galea@soton.ac.uk.

PMID: 30952792
PMCID: PMC6512887
DOI: 10.1212/WNL.0000000000007397

Abstract

Objective: To perform an individual patient-level data (IPLD) analysis and to determine the relationship between haptoglobin (HP) genotype and outcomes after aneurysmal subarachnoid hemorrhage (aSAH).

Methods: The primary outcome was favorable outcome on the modified Rankin Scale or Glasgow Outcome Scale up to 12 months after ictus. The secondary outcomes were occurrence of delayed ischemic neurologic deficit, radiologic infarction, angiographic vasospasm, and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons (WFNS) scale, Fisher grade, age, and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As preplanned, a 2-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) 1-stage analysis; (7) exclusion of studies not in Hardy-Weinberg equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; and (10) including only covariates significant in univariate analysis.

Results: Eleven studies (5 published, 6 unpublished) totaling 939 patients were included. Overall, the study population was in HWE. Follow-up times were 1, 3, and 6 months for 355, 516, and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis, higher age and WFNS scale were associated with an unfavorable outcome as expected.

Conclusion: This comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH.

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Figures

**Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses–Individual Patient Data (IPD) flow diagram**

**Figure 2. Forest plots for 2-stage individual patient–level data analysis for primary outcome (dichotomized modified Rankin Scale score in HP2-2 vs HP2-1 and HP1-1)**
An odds ratio (OR) >1 denotes a higher probability of poor outcome. (A) Adjusted for covariates, (B) same as A but including published studies only, and (C) unadjusted for covariates. CI = confidence interval; HP = haptoglobin; ID = identifier.

**Figure 3. Forest plots for 2-stage individual patient–level data analysis for secondary outcomes adjusted for covariates (HP2-2 vs HP2-1 and HP1-1)**
An odds ratio (OR) >1 denotes a higher probability of poor outcome. (A) Delayed cerebral ischemia, (B) radiologic infarction, (C) angiographic evidence of vasospasm, and (D) transcranial Doppler evidence of vasospasm. CI = confidence interval; HP = haptoglobin; ID = identifier.

**Figure 4. Forest plots for secondary outcomes, adjusted for covariates, published studies only (HP2-2 vs HP2-1 and HP1-1)**
An odds ratio (OR) >1 denotes a higher probability of poor outcome. (A) Delayed cerebral ischemia, (B) radiologic infarction, (C) angiographic evidence of vasospasm, and (D) transcranial Doppler evidence of vasospasm. CI = confidence interval; HP = haptoglobin; ID = identifier.

**Figure 5. Forest plots for secondary outcomes, unadjusted for covariates (HP2-2 vs HP2-1 and HP1-1)**
An odds ratio (OR) >1 denotes a higher probability of poor outcome. (A) Delayed cerebral ischemia, (B) radiologic infarction, (C) angiographic evidence of vasospasm, and (D) transcranial Doppler evidence of vasospasm. CI = confidence interval; HP = haptoglobin; ID = identifier.

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Comment in

Haptoglobin and hemoglobin in subarachnoid hemorrhage: A tale of 2 globins.
Macdonald RL, Katan M. Macdonald RL, et al. Neurology. 2019 Apr 30;92(18):831-832. doi: 10.1212/WNL.0000000000007399. Epub 2019 Apr 5. Neurology. 2019. PMID: 30952791 No abstract available.

References

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Haptoglobin genotype and aneurysmal subarachnoid hemorrhage: Individual patient data analysis

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Haptoglobin genotype and aneurysmal subarachnoid hemorrhage: Individual patient data analysis

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