Peter Izmirly1, Mimi Kim2, Deborah M Friedman3, Nathalie Costedoat-Chalumeau4, Robert Clancy5, Joshua A Copel6, Colin K L Phoon5, Bettina F Cuneo7, Rebecca E Cohen5, Kimberly Robins5, Mala Masson5, Benjamin J Wainwright5, Noel Zahr8, Amit Saxena5, Jill P Buyon9. 1. New York University School of Medicine, New York, New York. Electronic address: Peter.Izmirly@nyulangone.org. 2. Albert Einstein College of Medicine, Bronx, New York. 3. New York Medical College, Valhalla, New York. 4. APHP, Hospital Cochin, Paris, France. 5. New York University School of Medicine, New York, New York. 6. Yale School of Medicine, New Haven, Connecticut. 7. University of Colorado School of Medicine, Aurora, Colorado. 8. Pitié-Salpêtrière University Hospital, Paris, France. 9. New York University School of Medicine, New York, New York. Electronic address: https://twitter.com/JillBuyonMD.
Abstract
BACKGROUND: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).
RCT Entities:
BACKGROUND: Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB). OBJECTIVES:Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB. METHODS: This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash. RESULTS: By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4). CONCLUSIONS: These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).
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